AMPK activators

ABSTRACT

This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists, super agonists, full agonists, or partial agonists.

CROSS—REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of US Provisional Application No.63/044,565 filed on Jun. 26, 2020, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is aserine/threonine kinase and is evolutionarily conserved from yeast tomammals. AMPK acts as an energy sensor and is activated by upstreamenzymes when the cellular ratio of adenosine 5′—monophosphate (AMP) toadenosine triphosphate (ATP) is elevated due to nutrient deprivation.Activated AMPK phosphorylates downstream substrates to promotecatabolism and impede anabolism, leading to ATP production and energyrestoration. AMPK activity can be altered due to numerous physiologicalfactors, such as hormones, cytokines and dietary nutrients, as well aspathological conditions such as obesity, chronic inflammation and type 2diabetes. AMPK activation can lead to lower hepatic glucose productionand plasma glucose levels. Thus, AMPK is an attractive target to treatvarious metabolic diseases.

Additionally, AMPK has beneficial effects for gut health, such asenhancing intestinal absorption, improving barrier function, suppressingcolorectal carcinogenesis, and reducing intestinal inflammation andmetabolic-related disease, and is important for the maintenance ofintestinal homeostasis. For example, AMPK activation enhancesparacellular junctions, nutrient transporters, autophagy and apoptosis,and suppresses inflammation and carcinogenesis in the intestine.Accordingly, AMPK is associated with the maintenance of tight junctionsin colonic epithelium and controls the progression of colitis.

In various mouse models of colitis, treatment with a direct AMPKactivator has been shown to be efficacious at restoring gut barrierfunction (see, for example, WO 2018/189683; Sun, X., et al. (2017), CellDeath and Differentiation, 24(5), 819-831; Xue, Y., et al. (2016), PLoSONE, 11(12), 1-18; and Sun, X., et al. (2017), Open Biology, 7(8). Thiseffect has also been recapitulated with metformin, which is an indirectAMPK activator having additional biological activities (see, forexample, WO 2018/161077; and Di Fusco, D., et al. (2018), ClinicalScience, 132(11). However, there are safety concerns with sustaineddirect AMPK activation, particularly in the heart. Chronic treatmentwith systemic, direct activators can lead to cardiac hypertrophy(concomitant with increased cardiac glycogen) in rodents and non-humanprimates (See, Myers, R. W., et al. (2017),

Science, 357(6350), 507-511). Additionally, human genetic polymorphismsin AMPK are associated with cardiac glycogen deposition, cardiachypertrophy and Wolff-Parkinson-White syndrome, a conditioncharacterized by electrocardiogram (ECG) abnormalities (see, Burwinkel,B., et al. (2005), Am Journal of Human Genetics, 76(6), 1034-1049). Dueto this risk of cardiac hypertrophy, treatment with known AMPKactivators, which are systemic in nature, is unsuitable to address theproblem of treating IBD, colitis, and other diseases with a leaky gutbarrier with a direct AMPK activator.

Direct AMPK activation in the intestine without systemic engagement hasnever been demonstrated or proposed until the instant disclosure. Allreported direct AMPK activators which have been optimized and enteredclinical studies (for example, PF-06409577 from Pfizer) or extensivepreclinical evaluation (for example, MK-3903 and MK-8722 from Merck) aresystemic AMPK activators and have been developed for systemicengagement, as is reflected in the routes of administration andbiological assays present in patent applications and publishedmanuscripts relating to direct AMPK activators. A delayed-releaseformulation has been investigated to deliver higher concentrations ofthe indirect AMPK activator metformin to the colon for treatment of IBD.However, metformin does not optimally activate AMPK, metformin has otheractivities, and this approach requires specific formulation development.Thus it is not an optimal solution to the problem.

Disclosed herein is the discovery and development of the firstgut-restricted, direct AMPK activators that do not require sophisticatedformulations to reach the target tissue and avoid systemic circulation.

BRIEF SUMMARY OF THE INVENTION

Disclosed herein, in some embodiments, are adenosine5′-monophosphate-activated protein kinase (5′ AMP-activated proteinkinase, AMPK) activators useful for the treatment of conditions ordisorders associated with AMPK. In some embodiments, the condition ordisorder is associated with the gut-brain axis. In some embodiments, thecondition or disorder is associated with systemic infection andinflammation from having a leaky gut barrier. In some embodiments, theAMPK activators are gut-restricted or selectively modulate AMPK locatedin the gut. In some embodiments, the condition is selected from thegroup consisting of: central nervous system (CNS) disorders includingmood disorders, anxiety, depression, affective disorders, schizophrenia,malaise, cognition disorders, addiction, autism, epilepsy,neurodegenerative disorders, Alzheimer's disease, and Parkinson'sdisease, Lewy Body dementia, episodic cluster headache, migraine, pain;metabolic conditions including diabetes and its complications such aschronic kidney disease/diabetic nephropathy, diabetic retinopathy,diabetic neuropathy, cardiovascular disease, metabolic syndrome,obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eatingand nutritional disorders including hyperphagia, cachexia, anorexianervosa, short bowel syndrome, intestinal failure, intestinalinsufficiency and other eating disorders; inflammatory disorders andautoimmune diseases such as inflammatory bowel disease, ulcerativecolitis, Crohn's disease, checkpoint inhibitor-induced colitis,psoriasis and celiac disease; necrotizing enterocolitis;gastrointestinal injury resulting from toxic insults such as radiationor chemotherapy; diseases/disorders of gastrointestinal barrierdysfunction including environmental enteric dysfunction; spontaneousbacterial peritonitis; allergy including food allergy, celiac sprue, andchildhood allergy; graft vs. host disease; functional gastrointestinaldisorders such as irritable bowel syndrome, functional dyspepsia,functional abdominal bloating/distension, functional diarrhea,functional constipation, and opioid-induced constipation; gastroparesis;nausea and vomiting; disorders related to microbiome dysbiosis, andother conditions involving the gut-brain axis.

Disclosed herein, in some embodiments, is a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein: X is —O—, —S—, —NR³—, —C(O)—, —C(O)O—**, —C(O)NR³—**,—NR³C(O)—**, —SO₂—, or —SO₂NR³—**;

wherein ** indicates the attachment point to G;

Y is N, CH, or CR²;

G is C₁-C₅ alkyl, —(CH₂)_(j)-(C₃-C₁₀ cycloalkyl), —(CH₂)_(j)-(C₄₋₁₀Cycloalkenyl), —(CH₂)_(j)-(aryl), —(CH₂)_(j)-(heteroaryl),—(CH₂)_(j)-(3- to 10-membered heterocycloalkyl), or —(CH₂)_(j)-(5- to10-membered heterocycloalkenyl), which is substituted with 1, 2, 3, or 4substituents selected from —(CH₂)_(h)—C(O)OR⁷, —(CH₂)_(h)—P(O)(R⁷)OR⁷,—(CH₂)_(h)—P(O)(OR⁷)₂, —(CH₂)_(h)—S(O)₂OR⁷, —and —(CH₂)_(h)OH; and isfurther optionally substituted with 1, 2, 3, or 4 substituents selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆fluoroalkyl, —O—(C₁-C₆ alkyl), ═O and ═S;

is aryl, heteroaryl, or absent; wherein if

is —C≡C—or absent, then p is 0;

is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C₅₋₁₀ Cycloalkenyl,or 5- to 10-membered heterocycloalkenyl;

D is K, -Z-NR⁵R⁶, or R^(c);

Z is —(CH₂)_(r)—, —(CH(CH₃)—, *—(CH₂)_(r)-C(═O)—, or *—(CH₂)r—S(═O)₂—,where * represents

attachment to

K is —SO₂OH, —S(O)OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —B(OR^(d))(OH), —NHC(O)H,—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)),—NHC(O)NH(R^(d)),

—N(R^(d))C(═N(R^(d))N(R^(d))₂, —N(R^(d))C(═NH)NHC(═NH)NH₂,

each R^(a) and R^(b) is independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)R¹³, —C(O)OR¹³, —C(O)OR¹⁴, —OC(O)R¹³, —C(O)NR¹⁴R¹⁴,—NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴, —NR¹⁴C(O)OR¹⁴,—OC(O)OR¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl,wherein the alkyl, alkenyl, akynyl, cycloalkyl, heterocycloalkyl,phenyl, or heteroaryl are unsubstituted or substituted by 1, 2, or 3halogen or —OH groups;

R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl,c₁₋₁₀ alkoxyl, or —[(C(R^(d))₂)_(s)-V]_(t)—R⁹; wherein each V isindependently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and alkoxyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺, K,and -Z-NR⁵R⁶; or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andalkoxyl is substituted by 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂;

each R^(d) is independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl;wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3halogen or —OH groups;

each R^(e) is independently C₁₋₆ alkyl or C₃₋₆ cycloalkyl; wherein thealkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or—OH groups;

R¹ is hydrogen or C₁-C_(b 4) alkyl;

each R² is independently halogen, —CN, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl,or C₃-C₆ cycloalkyl;

R³ is hydrogen or C₁-C₄ alkyl;

R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups;

or R⁵ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ Cycloalkyl,C₅₋₁₀ cycloalkenyl, 3- to 8-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl; wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or whereinthe alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,or heterocycloalkenyl is substituted by 2-6 groups selected from —CO₂H,—OH, and —N(R^(d))₂; and wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl isoptionally further substituted by 1, 2, or 3 R^(f) groups;

each R^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)R¹³, —C(O)OR¹⁴, —OC(O)R¹³, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴, —NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the alkyl,alkenyl, akynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl areunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;

or R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C*R^(d))₂NR^(d)—, —C(R^(d))₂—, —N(R^(d)—2)-—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)-;

or R⁵ is —(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)-heteroaryl;wherein the aryl or heteroaryl is substituted by 1-6 groups selectedfrom —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein thealkylene is unsubstituted or substituted by 1, 2, or 3 R^(f) groups; R⁶is hydrogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; wherein the alkyl andcycloalkyl are unsubstituted or substituted by 1-3 groups independentlyselected from halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)R¹³, —C(O)OR¹⁴,—OC(O)R¹³, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴—NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴,—NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, or —P(O)(OR¹⁴)₂;

or R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 1-6 groups selected from —CH₃, —CH₂OH,—CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; or with 2-6groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂;

each R⁷ is independently hydrogen or C₁-C₄ alkyl;

R⁹ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₅₋₈ cycloalkenyl, 3 - to 8-membered heterocycloalkyl, phenyl, naphthyl,monocyclic heteroaryl, or bicyclic heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl phenyl,naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl is unsubstitutedor substituted by 1-6 groups selected from —OH, —CO₂H, —N(R^(e))₂,—N(R^(e))₃ ⁺, and K;

each R^(—)is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-membered heterocycloalkyl,phenyl, or monocyclic heteroaryl; and

each R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl; or two R¹⁴ on thesame nitrogen atom are taken together with the nitrogen to which theyare attached to form a 3- to 6-membered N-heterocycloalkyl;

each h is independently 0-4;

j is 0-4;

n is 0-2;

p is 0-3;

q is 0-3;

r is 0-3;

each s is independently 1-6; and

each t is independently 1-6.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments, Y is N or CH; R¹ is hydrogen or methyl; and each R²is independently —F, —Cl, —CN, methyl, ethyl, isopropyl, or —CF₃. Insome embodiments, Y is N; R¹ is hydrogen; R² is —F, —Cl, or —CN; and nis 1.

In some embodiments,

is aryl or heteroaryl; and

is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C₅₋₁₀ Cycloalkenyl,or 5- to 10-membered heterocycloalkenyl. In some embodiments,

is phenyl or 5- or 6-membered monocyclic heteroaryl; and

is phenyl, 5- or 6-membered monocyclic heteroaryl, C₃-C₆ cycloalkyl, 3-to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, is acompound of Formula (II):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein:

is phenyl, C₃-C₆ cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to10-membered bicyclic heterocycloalkenyl.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, is acompound of Formula (III):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof

In some embodiments, each R^(a) and R^(b) is independently halogen, —CN,—OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, or C₁-C₆fluoroalkyl; p is 0 or 1; and q is 0 or 1. In some embodiments, p is 0;and q is 0.

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, is acompound of Formula (IV):

-   -   or a pharmaceutically acceptable salt, solvate, stereoisomer, or        prodrug thereof.

In some embodiments, X is —O—, —S—, —NR³—, —C(O)NR³—**, —NR³C(O)—**, or—SO₂NR³—**; wherein ** indicates the attachment point to G; and R³ ishydrogen or methyl. In some embodiments, X is —O—or —S—. In someembodiments, X is —O—.

In some embodiments, G is C₁-C₅ alkyl, C₃-C₁₀ Cycloalkyl, —CH₂—(C₃—C₁₀cycloalkyl), aryl, 3-to 10-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4substituents selected from —(CH₂)_(h)-C(O)OR⁷, —(CH₂)_(h)—P(O)(R⁷)OR⁷,—(CH₂)_(h)—P(O)(OR⁷)₂, —(CH₂)_(h)—S(O)₂OR⁷, -and —(CH₂)_(h)OH; and isfurther optionally substituted with 1, 2, 3, or 4 substituents selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆fluoroalkyl, and —O—(C₁-C₆ alkyl); each R⁷ is independently hydrogen,methyl, or ethyl; and h is 0-1. In some embodiments, G is C₁-C₅ alkyl,C₃-C₁₀ Cycloalkyl, —CH₂—(C₃-C₁₀ cycloalkyl), aryl, 3- to 10-memberedheterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, which issubstituted with 1, 2, 3, or 4 substituents selected from —C(O)OH,—CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; and isfurther optionally substituted with 1, 2, 3, or 4 substituents selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆fluoroalkyl, and —O-(C₁-C₆ alkyl). In some embodiments, G is 3- to10-membered heterocycloalkyl, which is substituted with 1, 2, 3, or 4substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, - S(O)₂OH, —OH, and —CH₂OH. In some embodiments, G ismonocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygen atom,which is substituted with 1 or 2 substituents selected from —C(O)OH,—CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH. In someembodiments, G is bicyclic 8- to 10-membered heterocycloalkyl containing2 oxygen atoms, which is substituted with 1 or 2 substituents selectedfrom —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and—CH₂OH. In some embodiments, G is C₁-C₅ alkyl, C₃-C₆ cycloalkyl,—CH₂-(C₃-C₆ cycloalkyl), or phenyl, which is substituted with 1, 2, 3,or 4 substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; and is further optionallysubstituted with 1 or 2 substituents selected from C₁-C₆ alkyl, C₃-C₆cycloalkyl, and C₁-C₆ hydroxyalkyl.

In some embodiments, —X—G is selected from:

In some embodiments, D is K or -Z-NR⁵R⁶.

In some embodiments, D is K. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).

In some embodiments, D is -Z-NR⁵R⁶. In some embodiments, Z is —(CH₂)—,—(CH(CH₃)—, —C(═O)—, or —S(═O)₂—. In some embodiments, R⁵ is C₆-C₁₀alkyl that is substituted by 5 to 9 —OH groups; and R⁶ is hydrogen orC₁₋₆ alkyl. In some embodiments, R⁵ is C₁₋₁₀ alkyl which is substitutedby 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6 groupsselected from —CO₂H, —OH, and —N(R^(d))₂; and is optionally furthersubstituted by 1, 2, or 3 R^(f) groups; each R^(f) is independentlyhalogen, —CN, —OH, —OR¹³, NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴,—NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, orphenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted orsubstituted by 1, 2, or 3 halogen or —OH groups; and R⁶ is hydrogen orC₁₋₆ alkyl, which is unsubstituted or substituted by 1-3 groupsindependently selected from halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,C(O)OR¹⁴, C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, or —P(O)(OR¹⁴)₂.In some embodiments, R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each Vis independently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—,—N(R^(d))—C(O)—N(R^(d))—, or —C(O)N(R^(d))—; each R^(d) is independentlyhydrogen or C₁₋₆ alkyl; R⁶ is hydrogen or C₁₋₆ alkyl; and R⁹ ishydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, ornaphthyl is unsubstituted or substituted by 1-6 groups selected from—OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K. In some embodiments, R⁵ is—(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl; wherein thearyl or heteroaryl is substituted by 1-6 groups selected from —CO₂H,—OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein the alkylene isunsubstituted or substituted by 1, 2, or 3 R^(f) groups; and R⁶ ishydrogen or C₁₋₆ alkyl. In some embodiments, R⁵ and R⁶ are takentogether with the nitrogen to which they are attached to form a 3- to6-membered N-heterocycloalkyl which is unsubstituted or substituted with1-6 groups selected from —CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; or with 2-6 groups selected from—CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, and —N(R^(d))₂.In some embodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and eachR^(d) is independently hydrogen or C₁₋₆ alkyl. In some embodiments, K is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe).

In some embodiments, D is

In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, is acompound of Formula (V):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein:R² is —F, —Cl, or —CN;X is O or S;G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygenatom, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;or G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygenatoms, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;D is K or -Z-NR⁵R⁶.

In some embodiments, D is K; K is —SO₂OH, —P(O)(OH)(R^(d)),—P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or—SO₂NHC(O)(R^(d)); and each R^(d) is independently hydrogen or C₁₋₆alkyl.

In some embodiments, D is -Z-NR⁵R⁶; Z is —(CH₂)—, —(CH(CH₃)—, —C(═O)—,or —S(═O)₂-; and R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OHgroups; or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groups selectedfrom —N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH,and —N(R^(d))₂; and is optionally further substituted by 1, 2, or 3R^(f) groups; or R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V isindependently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—,or —C(O)N(R^(d))—; each R^(d) is independently hydrogen or C₁₋₆ alkyl;R⁹ is hydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl,phenyl, or naphthyl is unsubstituted or substituted by 1-6 groupsselected from —OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K; or R⁵ is—(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl; wherein thearyl or heteroaryl is substituted by 1-6 groups selected from —CO₂H,—OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein the alkylene isunsubstituted or substituted by 1, 2, or 3 R^(f) groups; R⁶ is hydrogenor C₁₋₆ alkyl, which is unsubstituted or substituted by 1-3 groupsindependently selected from halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, or—P(O)(OR¹⁴)₂; and or R⁵ and R⁶ are taken together with the nitrogen towhich they are attached to form a 4- to 6-membered N-heterocycloalkylwhich is unsubstituted or substituted with 1-6 groups selected from—CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; orwith 2-6 groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂; each R^(f) is independently halogen, —CN,—OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl, wherein thealkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2,or 3 halogen or —OH groups. In some embodiments, R⁵ is C₆-C₁₀ alkyl thatis substituted by 5 to 9 —OH groups; and R⁶ is hydrogen or C₁₋₆ alkyl.

In some embodiments, D is

Also disclosed herein, in some embodiment is a compound of Formula(III):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein:

X is —O—or —S-;

Y is N or CH;

G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygenatom, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;or G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygenatoms, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;

D is K or -Z-NR⁵R⁶;

Z is —(CH₂)—, —(CH(CH₃)—, —C(═O)—, or —S(═O)₂-;

K is —SO₂OH, —S(O)OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —B(OR^(d))(OH), —NHC(O)H,—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)),—NHC(O)NH(R^(d)),

—N(R^(d))C(═N(R^(d))N(R^(d))₂, —N(R^(d))C(═NH)NHC(═NH)NH₂,

R^(a) and R^(b) are each independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl;

each R^(d) is independently hydrogen or C₁₋₆ alkyl;

each R^(e) is independently C₁₋₆ alkyl;

each R² is independently halogen, —CN, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl,or C₃-C₆ cycloalkyl;

R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups;

or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groups selected from—N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH, and—N(R^(d)); and is optionally further substituted by 1, 2, or 3 R^(f)groups;

each R^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴ ,—C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴ C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl,is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;

or R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—, or—C(O)N(R^(d))—;

or R⁵ is —(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl;wherein the aryl or heteroaryl is substituted by 1-6 groups selectedfrom —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein thealkylene is unsubstituted or substituted by 1, 2, or 3 R^(f) groups;

R⁶ is hydrogen or C₁₋₆ alkyl;

or R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 1-6 groups selected from —CH₃, —CH₂OH,—CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; or with 2-6groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂;

R⁹ is hydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl,phenyl, or naphthyl is unsubstituted or substituted by 1-6 groupsselected from —OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K;

each R¹³ is independently c₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,0-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-membered heterocycloalkyl,phenyl, or monocyclic heteroaryl; and

each R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl;

or two R¹⁴ on the same nitrogen atom are taken together with thenitrogen to which they are attached to form a 3- to 6-memberedN-heterocycloalkyl;

p is 0 or 1;

q is 0 or 1;

each s is independently 1-6; and

each t is independently 1-6.

In some embodiments, R² is —F, —Cl, or —CN; r^(a) is —F, —Cl, —CN, —OH,—OCH₃, —OCF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, —CH₂F, —CHF2, or —CF₃; and R^(b) is —F, —Cl, —CN,—OH, —OCH₃, —OCF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, —CH₂F, —CHF₂, or —CF₃.

In some embodiments, the compound of Formula (III), or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, is a compound of Formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.

In some embodiments, X is —O—.

In some embodiments, G is monocyclic 3- to 6-membered heterocycloalkylcontaining 1 oxygen atom, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is bicyclic 8- to 10-memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1or 2 substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH.

In some embodiments, —X—G is selected from:

In some embodiments, Y is N. In some embodiments, Y is CH.

In some embodiments, D is K; and K is —SO₂OH, —P(O)(OH)(R^(d)),—P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or—SO₂NHC(O)(R^(d)).

In some embodiments, D is -Z-NR⁵R⁶. In some embodiments, Z is —(CH₂)—,—C(═O)—, or —S(═O)₂—. In some embodiments, R⁵ is C₆-C₁₀ alkyl that issubstituted by 5 to 9 —OH groups. In some embodiments, R⁵ is C₁₋₁₀ alkylwhich is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; orwith 2-6 groups selected from —CO₂H, —OH, and —N(R^(d))₂; and isoptionally further substituted by 1, 2, or 3 R^(f) groups; and eachR^(f) is independently halogen, —CN, —OH, —OR¹³, NR¹⁴R¹⁴, —C(O)OR¹⁴,—C(O)NR¹⁴R¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, isunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups. Insome embodiments, R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V isindependently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—,or —C(O)N(R^(d))—; each R^(d) is independently hydrogen or C₁₋₆ alkyl;R⁶ is hydrogen or C₁₋₆ alkyl; and R⁹ is hydrogen, C₁₋₈ alkyl, phenyl, ornaphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted orsubstituted by 1-6 groups selected from —OH, —CO₂H, —N(R^(e))₂,—N(R^(e))₃ ⁺, and K. In some embodiments, R⁵ and R⁶ are taken togetherwith the nitrogen to which they are attached to form a 3- to 6-memberedN-heterocycloalkyl which is unsubstituted or substituted with 1-6 groupsselected from —CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH,—N(R^(e))₃ ⁺, and K; or with 2-6 groups selected from —CO₂H, —OH,—CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, and —N(R^(d))₂. In someembodiments, R⁵ and R⁶ are taken together with the nitrogen to whichthey are attached to form a 4- to 6-membered N-heterocycloalkyl which issubstituted with 2-4 groups selected from —OH and —CH₂OH. In someembodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OHgroups; or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groups selectedfrom —N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH,and —N(R^(d))₂; and is optionally further substituted by 1, 2, or 3R^(f) groups. In some embodiments, K is —SO₂OH, —P(O)(OH)(R^(d)),—P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or—SO₂NHC(O)(R^(d)). In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or —P(O)(OH)₂.

In some embodiments, D is

Disclosed herein, in some embodiments, are pharmaceutical compositionscomprising a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof, and at least onepharmaceutically acceptable excipient.

Disclosed herein, in some embodiments, are methods of treating anadenosine 5′-monophosphate-activated protein kinase (AMPK) associatedcondition or disorder in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof. In some embodiments,the condition or disorder involves the gut-brain axis. In someembodiments, the condition or disorder is a nutritional disorder. Insome embodiments, the condition or disorder is short bowel syndrome,intestinal failure, or intestinal insufficiency. In some embodiments,the condition or disorder is associated with systemic infection andinflammation from having a leaky gut barrier. In some embodiments, thecondition or disorder is metabolic syndrome, obesity, type 2 diabetes,coronary artery disease, fatty liver, nonalcoholic steatohepatitis(NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders includingscleroderma, inflammatory bowel disease including Crohn's disease,ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis,celiac disease, necrotizing enterocolitis, gastrointestinal injuryresulting from toxic insults such as radiation or chemotherapy,environmental enteric dysfunction, allergy including food allergy,celiac sprue, and childhood allergy, graft vs. host disease, irritablebowel syndrome, spontaneous bacterial peritonitis, ischemic colitis,sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancerincluding colorectal cancer, depression, autism, or a combinationthereof.

Also disclosed herein, in some embodiments, are methods of treatinggastrointestinal injury resulting from toxic insult, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound disclosed herein, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof. In some embodiments,the toxic insult is from radiation, chemotherapy, or a combinationthereof. In some embodiments, the toxic insult is radiation-induced. Insome embodiments, the toxic insult is chemotherapy-induced.

Also disclosed herein, in some embodiments, is the use of a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, as a medicine.

Also disclosed herein, in some embodiments, is the use of a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, for the treatment of an adenosine5′-monophosphate-activated protein kinase (AMPK) associated condition ordisorder in a subject in need thereof. In some embodiments, thecondition or disorder involves the gut-brain axis. In some embodiments,the condition or disorder is a nutritional disorder. In someembodiments, the condition or disorder is short bowel syndrome,intestinal failure, or intestinal insufficiency. In some embodiments,the condition or disorder is associated with systemic infection andinflammation from having a leaky gut barrier. In some embodiments, thecondition or disorder is metabolic syndrome, obesity, type 2 diabetes,coronary artery disease, fatty liver, nonalcoholic steatohepatitis(NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders includingscleroderma, inflammatory bowel disease including Crohn's disease,ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis,celiac disease, necrotizing enterocolitis, gastrointestinal injuryresulting from toxic insults such as radiation or chemotherapy,environmental enteric dysfunction, allergy including food allergy,celiac sprue, and childhood allergy, graft vs. host disease, irritablebowel syndrome, spontaneous bacterial peritonitis, ischemic colitis,sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancerincluding colorectal cancer, depression, autism, or a combinationthereof.

Also disclosed herein, in some embodiments, is the use of a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, for the treatment of gastrointestinalinjury resulting from toxic insult in a subject in need thereof. In someembodiments, the toxic insult is from radiation, chemotherapy, or acombination thereof. In some embodiments, the toxic insult isradiation-induced. In some embodiments, the toxic insult ischemotherapy-induced.

Also disclosed herein, in some embodiments, is the use of a compounddisclosed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, for the preparation of a medicamentfor the treatment of the diseases disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

This disclosure is directed, at least in part, to AMPK activators usefulfor the treatment of conditions or disorders involving the gut-brainaxis. In some embodiments, the AMPK activators are gut-restrictedcompounds. In some embodiments, the AMPK activators are agonists, superagonists, full agonists, or partial agonists.

Compounds disclosed herein directly activate AMPK in the intestinewithout systemic engagement. The preferred compounds are more potent,efficacious at lower doses, and have decreased systemic exposurecompared to other previously-known AMPK activators.

Definitions

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “an agent” includes aplurality of such agents, and reference to “the cell” includes referenceto one or more cells (or to a plurality of cells) and equivalentsthereof known to those skilled in the art, and so forth. When ranges areused herein for physical properties, such as molecular weight, orchemical properties, such as chemical formulas, all combinations andsubcombinations of ranges and specific embodiments therein are intendedto be included.

The term “about” when referring to a number or a numerical range meansthat the number or numerical range referred to is an approximationwithin experimental variability (or within statistical experimentalerror), and thus the number or numerical range, in some instances, willvary between 1% and 15% of the stated number or numerical range.

The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatin other embodiments, for example, an embodiment of any composition ofmatter, composition, method, or process, or the like, described herein,“consist of” or “consist essentially of” the described features.

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below:

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e., groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, andt-butyl.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched- chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, or more preferably, from oneto six carbon atoms, wherein an sp^(a)-hybridized carbon of the alkylresidue is attached to the rest of the molecule by a single bond.Examples include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl, and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl”means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, althoughthe present definition also covers the occurrence of the term “alkyl”where no numerical range is designated. In some embodiments, the alkylis a C₁-C₁₀ alkyl, a C₁-C₉ alkyl, a C₁-C₈ alkyl, a C₁-C₇ alkyl, a C₁-C₆alkyl, a C₁-C₅ alkyl, a C₁-C₄ alkyl, a C₁-C₃ alkyl, a C₁-C₂ alkyl, or aC₁ alkyl. Unless stated otherwise specifically in the specification, analkyl group is optionally substituted as described below by one or moreof the following substituents: halo, cyano, nitro, oxo, thioxo, imino,oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)R^(a), —OC(O)—OR^(f),—N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms, wherein ansp²-hybridized carbon or an sp³-hybridized carbon of the alkenyl residueis attached to the rest of the molecule by a single bond. The group maybe in either the cis or trans conformation about the double bond(s), andshould be understood to include both isomers. Examples include, but arenot limited to ethenyl (—CH═CH₂), n-propenyl (—CH═CHCH₃, —CH₂CH═CH₂),isopropenyl (—C(CH₃)═CH₂), butenyl, 1,3-butadienyl and the like.Whenever it appears herein, a numerical range such as “C₂-C₆ alkenyl”means that the alkenyl group may consist of 2 carbon atoms, 3 carbonatoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although thepresent definition also covers the occurrence of the term “alkenyl”where no numerical range is designated. In some embodiments, the alkenylis a C₂-C₁₀ alkenyl, a C₂-C₉ alkenyl, a C₂-C₈ alkenyl, a C₂-C₇ alkenyl,a C₂-C₆ alkenyl, a C₂-C₅ alkenyl, a C₂-C₄ alkenyl, a C₂-C₃ alkenyl, or aC2 alkenyl. Unless stated otherwise specifically in the specification,an alkenyl group is optionally substituted as described below, forexample, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl,alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.Unless stated otherwise specifically in the specification, an alkenylgroup is optionally substituted as described below by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —OC(O)—OR^(f),—N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) where t is 1or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂ (wheret is 1 or 2) where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms,wherein an sp-hybridized carbon or an sp^(a)-hybridized carbon of thealkynyl residue is attached to the rest of the molecule by a singlebond. Examples include, but are not limited to ethynyl, 2-propynyl,2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, anumerical range such as “C₂-C₆ alkynyl” means that the alkynyl group mayconsist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbonatoms or 6 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.In some embodiments, the alkynyl is a C₂-C₁₀ alkynyl, a C₂-C₉ alkynyl, aC₂-C₈ alkynyl, a C₂-C₇ alkynyl, a C₂-C₆ alkynyl, a C₂-C₅ alkynyl, aC₂-C₄ alkynyl, a C₂-C₃ alkynyl, or a C2 alkynyl. Unless stated otherwisespecifically in the specification, an alkynyl group is optionallysubstituted as described below by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)R^(a), —OC(O)—OR^(f),—N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)O(R^(a)) (where tis 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group arethrough one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene group is optionally substituted as describedbelow by one or more of the following substituents: halo, cyano, nitro,oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)R^(a), —OC(O)—OR^(f), —N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a),—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂,—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)O(R^(a)) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R^(f) isindependently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon double bond, and having from two to twelve carbon atoms.The alkenylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. Unlessstated otherwise specifically in the specification, an alkenylene groupis optionally substituted as described below by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(f), —OC(O)—OR^(f),—N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl.

“Alkynylene” or “alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onecarbon-carbon triple bond, and having from two to twelve carbon atoms.The alkynylene chain is attached to the rest of the molecule through asingle bond and to the radical group through a single bond. Unlessstated otherwise specifically in the specification, an alkynylene groupis optionally substituted as described below by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)R^(a), —OC(O)—OR^(f),—N(R^(a))₂, —N⁺(R^(a))₃, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)O(R^(a)) (where tis 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl.

“Alkoxy” or “alkoxyl” refers to a radical bonded through an oxygen atomof the formula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from 6 to 18 carbon atoms,where at least one of the rings in the ring system is fully unsaturated,i.e., it contains a cyclic, delocalized (4n+2) π-electron system inaccordance with the Hückel theory. The ring system from which arylgroups are derived include, but are not limited to, groups such asbenzene, fluorene, indane, indene, tetralin and naphthalene. In someembodiments, the aryl is a C₆-C₁₀ aryl. In some embodiments, the aryl isa phenyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted as described below by oneor more substituents independently selected from alkyl, alkenyl,alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl,aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(f),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—N⁺(R^(a))₃,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)-C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))_(2, —R) ^(b)—N(R^(a))C(O)OR^(f),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(f) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(f)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, R^(f) is independently alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl (optionally substituted with one or more halogroups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

An “arylene” refers to a divalent radical derived from an “aryl” groupas described above linking the rest of the molecule to a radical group.The arylene is attached to the rest of the molecule through a singlebond and to the radical group through a single bond. In someembodiments, the arylene is a phenylene. Unless stated otherwisespecifically in the specification, an arylene group is optionallysubstituted as described above for an aryl group.

“Cycloalkyl” refers to a stable, partially or fully saturated,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems.Representative cycloalkyls include, but are not limited to, cycloalkylshaving from three to fifteen carbon atoms (C₃-C₁₅ cycloalkyl), fromthree to ten carbon atoms (C₃-C₁₀ cycloalkyl), from three to eightcarbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆cycloalkyl), from three to five carbon atoms (C₃-05 cycloalkyl), orthree to four carbon atoms (C₃-C₄ cycloalkyl). In some embodiments, thecycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, thecycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkylsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocyclesinclude, for example, adamantyl, norbornyl, decalinyl,bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl,cis-decalyl, trans-decalyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl,7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless otherwise statedspecifically in the specification, the term “cycloalkyl” is meant toinclude cycloalkyl radicals optionally substituted as described below byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl,aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b),—OC(O)—OR^(f),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—N⁺(R^(a))₃,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(f),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)N(R^(a))S(O)_(t)R^(f) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(f)(where t is 1 or 2) and —R^(b)—S(O))_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, R^(f) is independently alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl (optionally substituted with one or more halogroups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

A “cycloalkylene” refers to a divalent radical derived from a“cycloalkyl” group as described above linking the rest of the moleculeto a radical group. The cycloalkylene is attached to the rest of themolecule through a single bond and to the radical group through a singlebond. Unless stated otherwise specifically in the specification, acycloalkylene group is optionally substituted as described above for acycloalkyl group.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen is fluoro or chloro. In some embodiments, halogenis fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, e.g., trifluoromethyl,difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

“Haloalkoxy” or “haloalkoxyl” refers to an alkoxyl radical, as definedabove, that is substituted by one or more halo radicals, as definedabove.

“Fluoroalkoxy” or “fluoroalkoxyl” refers to an alkoxy radical, asdefined above, that is substituted by one or more fluoro radicals, asdefined above, for example, trifluoromethoxy, difluoromethoxy,fluoromethoxy, and the like.

“Hydroxyalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more hydroxyl radicals, as defined above, e.g.,hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl,2,3,4,5,6-pentahydroxyhexyl, and the like.

“Heterocycloalkyl” refers to a stable 3- to 24-membered partially orfully saturated ring radical comprising 2 to 23 carbon atoms and fromone to 8 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fused(when fused with an aryl or a heteroaryl ring, the heterocycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems; andthe nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical maybe optionally oxidized; the nitrogen atom may be optionally quaternized.In some embodiments, the heterocycloalkyl is a 3- to 8-memberedheterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to6-membered heterocycloalkyl. In some embodiments, the heterocycloalkylis a 5- to 6-membered heterocycloalkyl. Examples of suchheterocycloalkyl radicals include, but are not limited to, aziridinyl,azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl,3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. Morepreferably, heterocycloalkyls have from 2 to 10 carbons in the ring. Itis understood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e., skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, the term “heterocycloalkyl” is meant to includeheterocycloalkyl radicals as defined above that are optionallysubstituted by one or more substituents selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)-OR³, —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(f), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—N⁺(R^(a))₃, —R^(b)-C(O)R^(a), ——R^(b)—C(O)OR^(a),—R^(b)-C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(f), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)-S(O)_(t)R^(f) (where t is 1 or 2) and—R^(b)—S(O))_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl, R^(f) is independentlyalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionallysubstituted with one or more halo groups), aralkyl, heterocycloalkyl,heteroaryl or heteroarylalkyl, each R^(b) is independently a direct bondor a straight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain.

“N-heterocycloalkyl” refers to a heterocycloalkyl radical as definedabove containing at least one nitrogen and where the point of attachmentof the heterocycloalkyl radical to the rest of the molecule is through anitrogen atom in the heterocycloalkyl radical. An N-heterocycloalkylradical is optionally substituted as described above forheterocycloalkyl radicals.

“C-heterocycloalkyl” refers to a heterocycloalkyl radical as definedabove and where the point of attachment of the heterocycloalkyl radicalto the rest of the molecule is through a carbon atom in theheterocycloalkyl radical. A C-heterocycloalkyl radical is optionallysubstituted as described above for heterocycloalkyl radicals.

A “heterocycloalkylene” refers to a divalent radical derived from a“heterocycloalkyl” group as described above linking the rest of themolecule to a radical group. The heterocycloalkylene is attached to therest of the molecule through a single bond and to the radical groupthrough a single bond. Unless stated otherwise specifically in thespecification, a heterocycloalkylene group is optionally substituted asdescribed above for a heterocycloalkyl group.

“Heteroaryl” refers to a radical derived from a 5- to 18-memberedaromatic ring radical that comprises one to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. In some embodiments, the heteroaryl is a 5- to 10-memberedheteroaryl. In some embodiments, the heteroaryl is a monocyclicheteroaryl, or a monocyclic 5- or 6-membered heteroaryl. In someembodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Unless stated otherwise specifically in the specification,the term “heteroaryl” is meant to include heteroaryl radicals as definedabove that are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo,cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)SR^(a), *—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(f),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—N⁺(R^(a))₃,—R^(b)-C(O)R^(a), —R^(b)-C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)-C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(f),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(f) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(f)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, R^(f) is independently alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl (optionally substituted with one or more halogroups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

A “heteroarylene” refers to a divalent radical derived from a“heteroaryl” group as described above linking the rest of the moleculeto a radical group. The heteroarylene is attached to the rest of themolecule through a single bond and to the radical group through a singlebond. Unless stated otherwise specifically in the specification, aheteroarylene group is optionally substituted as described above for aheteroaryl group.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be unsubstituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF2, —CH₂CF₃, —CF₂CH₃,—CFHCHF2, etc.). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible.

The term “modulate” or “modulating” or “modulation” refers to anincrease or decrease in the amount, quality, or effect of a particularactivity, function or molecule. By way of illustration and notlimitation, activators, agonists, partial agonists, inverse agonists,antagonists, inhibitors, and allosteric modulators of an enzyme aremodulators of the enzyme.

The term “agonism” as used herein refers to the activation of a receptoror enzyme by a modulator, or agonist, to produce a biological response.

The term “agonist” or “activator” as used herein refers to a modulatorthat binds to a receptor or target enzyme and activates the receptor orenzyme to produce a biological response. By way of example, “AMPKactivator” can be used to refer to a compound that exhibits an EC₅₀ withrespect to AMPK activity of no more than about 100 μM, as measured inthe pAMPK1 kinase activation assay. In some embodiments, the term“agonist” includes super agonists, full agonists or partial agonists.

The term “super agonist” as used herein refers to a modulator that iscapable of producing a maximal response greater than the endogenousagonist for the target receptor or enzyme, and thus has an efficacy ofmore than 100%.

The term “full agonist” refers to a modulator that binds to andactivates a receptor or target enzyme with the maximum response that anendogenous agonist can elicit at the receptor or enzyme.

The term “partial agonist” refers to a modulator that binds to andactivates a receptor or target enzyme, but has partial efficacy, thatis, less than the maximal response, at the receptor or enzyme relativeto a full agonist.

The term “positive allosteric modulator” refers to a modulator thatbinds to a site distinct from the orthosteric binding site and enhancesor amplifies the effect of an agonist.

The term “antagonism” or “inhibition” as used herein refers to theinactivation of a receptor or target enzyme by a modulator, orantagonist. Antagonism of a receptor, for example, is when a moleculebinds to the receptor or target enzyme and does not allow activity tooccur.

The term “antagonist” or “neutral antagonist” or “inhibitor” as usedherein refers to a modulator that binds to a receptor or target enzymeand blocks a biological response. An antagonist has no activity in theabsence of an agonist or inverse agonist but can block the activity ofeither, causing no change in the biological response.

The term “inverse agonist” refers to a modulator that binds to the samereceptor or target enzyme as an agonist but induces a pharmacologicalresponse opposite to that agonist, i.e., a decrease in biologicalresponse.

The term “negative allosteric modulator” refers to a modulator thatbinds to a site distinct from the orthosteric binding site and reducesor dampens the effect of an agonist.

As used herein, “EC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%activation or enhancement of a biological process. In some instances,EC₅₀ refers to the concentration of agonist that provokes a responsehalfway between the baseline and maximum response in an in vitro assay.In some embodiments as used herein, EC₅₀ refers to the concentration ofan activator (e.g., an AMPK activator) that is required for 50%activation of AMPK.

As used herein, “IC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process. For example, IC₅₀ refers to the halfmaximal (50%) inhibitory concentration (IC) of a substance as determinedin a suitable assay. In some instances, an IC₅₀ is determined in an invitro assay system. In some embodiments as used herein, IC₅₀ refers tothe concentration of a modulator (e.g., an antagonist or inhibitor) thatis required for 50% inhibition of a receptor or a target enzyme.

The terms “subject,” “individual,” and “patient” are usedinterchangeably. These terms encompass mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike.

The term “gut-restricted” as used herein refers to a compound, e.g., anAMPK activator, that is predominantly active in the gastrointestinalsystem. In some embodiments, the biological activity of thegut-restricted compound, e.g., a gut-restricted AMPK activator, isrestricted to the gastrointestinal system. In some embodiments,gastrointestinal concentration of a gut-restricted modulator, e.g., agut-restricted AMPK activator, is higher than the IC₅₀ value or the EC₅₀value of the gut-restricted modulator against its receptor or targetenzyme, e.g., AMPK, while the plasma levels of said gut-restrictedmodulator, e.g., gut-restricted AMPK activator, are lower than the ICsovalue or the EC₅₀ value of the gut-restricted modulator against itsreceptor or target enzyme, e.g., AMPK. In some embodiments, thegut-restricted compound, e.g., a gut-restricted AMPK activator, isnon-systemic. In some embodiments, the gut-restricted compound, e.g., agut-restricted AMPK activator, is a non-absorbed compound. In otherembodiments, the gut-restricted compound, e.g., a gut-restricted AMPKactivator, is absorbed, but is rapidly metabolized to metabolites thatare significantly less active than the modulator itself toward thetarget receptor or enzyme, i.e., a “soft drug.” In other embodiments,the gut-restricted compound, e.g., a gut-restricted AMPK activator, isminimally absorbed and rapidly metabolized to metabolites that aresignificantly less active than the modulator itself toward the targetreceptor or enzyme. In some embodiments, the gut-restricted AMPKactivator has high efflux. In other embodiments, the gut-restricted AMPKactivator is a substrate for one or more intestinal efflux transporterssuch as P-gp (MDR¹), BCRP, or MRP2.

In some embodiments, the gut-restricted modulator, e.g., agut-restricted AMPK activator, is non-systemic but is instead localizedto the gastrointestinal system. For example, the modulator, e.g., agut-restricted AMPK activator, may be present in high levels in the gut,but low levels in serum. In some embodiments, the systemic exposure of agut-restricted modulator, e.g., a gut-restricted AMPK activator, is, forexample, less than 100, less than 50, less than 20, less than 10, orless than 5 nM, bound or unbound, in blood serum. In some embodiments,the intestinal exposure of a gut-restricted modulator, e.g., agut-restricted AMPK activator, is, for example, greater than 1000, 5000,10000, 50000, 100000, or 500000 nM. In some embodiments, a modulator,e.g., a gut-restricted AMPK activator, is gut-restricted due to poorabsorption of the modulator itself, or because of absorption of themodulator which is rapidly metabolized in serum resulting in lowsystemic circulation, or due to both poor absorption and rapidmetabolism in the serum. In some embodiments, a modulator, e.g., agut-restricted AMPK activator, is covalently bonded to a kinetophore,optionally through a linker, which changes the pharmacokinetic profileof the modulator.

In other embodiments, the gut-restricted modulator is a soft drug. Theterm “soft drug” as used herein refers to a modulator that isbiologically active but is rapidly metabolized to metabolites that aresignificantly less active than the modulator itself toward the targetreceptor. In some embodiments, the gut-restricted modulator is a softdrug that is rapidly metabolized in the blood to significantly lessactive metabolites. In some embodiments, the gut-restricted modulator isa soft drug that is rapidly metabolized in the liver to significantlyless active metabolites. In some embodiments, the gut-restrictedmodulator is a soft drug that is rapidly metabolized in the blood andthe liver to significantly less active metabolites. In some embodiments,the gut-restricted modulator is a soft drug that has low systemicexposure. In some embodiments, the biological activity of themetabolite(s) is/are 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or1000-fold lower than the biological activity of the soft druggut-restricted modulator.

The term “kinetophore” as used herein refers to a structural unittethered to a small molecule modulator, e.g., an AMPK activator,optionally through a linker, which makes the whole molecule larger andincreases the polar surface area while maintaining biological activityof the small molecule modulator. The kinetophore influences thepharmacokinetic properties, for example solubility, absorption,distribution, rate of elimination, and the like, of the small moleculemodulator, e.g., an AMPK activator, and has minimal changes to thebinding to or association with a receptor or target enzyme. The definingfeature of a kinetophore is not its interaction with the target, forexample an enzyme, but rather its effect on specific physiochemicalcharacteristics of the modulator to which it is attached, e.g., an AMPKactivator. In some instances, kinetophores are used to restrict amodulator, e.g., an AMPK activator, to the gut.

The term “linked” as used herein refers to a covalent linkage between amodulator, e.g., an AMPK activator, and a kinetophore. The linkage canbe through a covalent bond, or through a “linker.” As used herein,“linker” refers to one or more bifunctional molecules which can be usedto covalently bonded to the modulator, e.g., an AMPK activator, andkinetophore. In some embodiments, the linker is attached to any part ofthe modulator, e.g., an AMPK activator, so long as the point ofattachment does not interfere with the binding of the modulator to itsreceptor or target enzyme. In some embodiments, the linker isnon-cleavable. In some embodiments, the linker is cleavable. In someembodiments, the linker is cleavable in the gut. In some embodiments,cleaving the linker releases the biologically active modulator, e.g., anAMPK activator, in the gut.

The term “gastrointestinal system” (GI system) or “gastrointestinaltract” (GI tract) as used herein, refers to the organs and systemsinvolved in the process of digestion. The gastrointestinal tractincludes the esophagus, stomach, small intestine, which includes theduodenum, jejunum, and ileum, and large intestine, which includes thececum, colon, and rectum. In some embodiments herein, the GI systemrefers to the “gut,” meaning the stomach, small intestines, and largeintestines or to the small and large intestines, including, for example,the duodenum, jejunum, and/or colon.

Gut-Brain Axis

The gut-brain axis refers to the bidirectional biochemical signalingthat connects the gastrointestinal tract (GI tract) with the centralnervous system (CNS) through the peripheral nervous system (PNS) andendocrine, immune, and metabolic pathways.

In some instances, the gut-brain axis comprises the GI tract; the PNSincluding the dorsal root ganglia (DRG) and the sympathetic andparasympathetic arms of the autonomic nervous system including theenteric nervous system and the vagus nerve; the CNS; and theneuroendocrine and neuroimmune systems including thehypothalamic-pituitary-adrenal axis (HPA axis). The gut-brain axis isimportant for maintaining homeostasis of the body and is regulated andmodulates physiology through the central and peripheral nervous systemsand endocrine, immune, and metabolic pathways.

The gut-brain axis modulates several important aspects of physiology andbehavior. Modulation by the gut-brain axis occurs via hormonal andneural circuits. Key components of these hormonal and neural circuits ofthe gut-brain axis include highly specialized, secretory intestinalcells that release hormones (enteroendocrine cells or EECs), theautonomic nervous system (including the vagus nerve and enteric nervoussystem), and the central nervous system. These systems work together ina highly coordinated fashion to modulate physiology and behavior.

Defects in the gut-brain axis are linked to a number of diseases,including those of high unmet need. Diseases and conditions affected bythe gut-brain axis, include central nervous system (CNS) disordersincluding mood disorders, anxiety, depression, affective disorders,schizophrenia, malaise, cognition disorders, addiction, autism,epilepsy, neurodegenerative disorders, Alzheimer's disease, andParkinson's disease, Lewy Body dementia, episodic cluster headache,migraine, pain; metabolic conditions including diabetes and itscomplications such as chronic kidney disease/diabetic nephropathy,diabetic retinopathy, diabetic neuropathy, cardiovascular disease,metabolic syndrome, obesity, dyslipidemia, and nonalcoholicsteatohepatitis (NASH); eating and nutritional disorders includinghyperphagia, cachexia, anorexia nervosa, short bowel syndrome,intestinal failure, intestinal insufficiency and other eating disorders;inflammatory disorders and autoimmune diseases such as inflammatorybowel disease, ulcerative colitis, Crohn's disease, checkpointinhibitor-induced colitis, psoriasis, celiac disease, and enteritis,including chemotherapy- induced enteritis or radiation-inducedenteritis; necrotizing enterocolitis; gastrointestinal injury resultingfrom toxic insults such as radiation or chemotherapy; diseases/disordersof gastrointestinal barrier dysfunction including environmental entericdysfunction, spontaneous bacterial peritonitis; allergy including foodallergy, celiac sprue, and childhood allergy; graft vs. host disease;functional gastrointestinal disorders such as irritable bowel syndrome,functional dyspepsia, functional abdominal bloating/distension,functional diarrhea, functional constipation, and opioid-inducedconstipation; gastroparesis; nausea and vomiting; disorders related tomicrobiome dysbiosis, and other conditions involving the gut-brain axis.

Adenosine 5′-Monophosphate-Activated Protein Kinase (AMPK) in theGut-Brain Axis

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is aserine/threonine kinase and is evolutionarily conserved from yeast tomammals. In some instances, AMPK is a heterotrimeric protein complexthat is formed by one α (α1 or α2), one β(β1 or β2), and one γ(γ1, γ2,or γ3) subunit. Due to the presence of isoforms of its components, thereare 12 versions of AMPK (AMPK1, AMPK2, etc., through AMPK12). In someinstances, AMPK acts as an energy sensor and is activated by upstreamenzymes when the cellular ratio of adenosine 5′—monophosphate (AMP) toadenosine triphosphate (ATP) is elevated due to nutrient deprivation. Insome instances, activated AMPK phosphorylates downstream substrates topromote catabolism and impede anabolism, leading to ATP production andenergy restoration. In some instances, AMPK activity can be altered dueto numerous physiological factors, such as hormones, cytokines anddietary nutrients, as well as pathological conditions such as obesity,chronic inflammation and type 2 diabetes. In some instances, AMPKactivation leads to lower hepatic glucose production and plasma glucoselevels. Thus, in some instances, AMPK activation can act as atherapeutic agent to treat various metabolic diseases.

In some instances, AMPK has beneficial effects for gut health, such asenhancing intestinal absorption, improving barrier function, suppressingcolorectal carcinogenesis, and reducing intestinal inflammation andmetabolic-related disease, and is important for the maintenance ofintestinal homeostasis. In some instances, AMPK is essential for properintestinal health. In some instances, AMPK activation enhancesparacellular junctions, nutrient transporters, autophagy and apoptosis,and suppresses inflammation and carcinogenesis in the intestine.

In some embodiments, this disclosure provides AMPK activators that canbe broadly used for multiple conditions and disorders associated withAMPK. In some embodiments, the condition or disorder is associated withthe gut-brain axis. In some embodiments, the condition or disorder is acentral nervous system (CNS) disorder including mood disorders, anxiety,depression, affective disorders, schizophrenia, malaise, cognitiondisorders, addiction, autism, epilepsy, neurodegenerative disorders,Alzheimer's disease, and Parkinson's disease, Lewy Body dementia,episodic cluster headache, migraine, pain; metabolic conditionsincluding diabetes and its complications such as chronic kidneydisease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy,cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, andnonalcoholic steatohepatitis (NASH); eating and nutritional disordersincluding hyperphagia, cachexia, anorexia nervosa, short bowel syndrome,intestinal failure, intestinal insufficiency and other eating disorders;inflammatory disorders and autoimmune diseases such as inflammatorybowel disease, ulcerative colitis, Crohn's disease, checkpointinhibitor-induced colitis, psoriasis, celiac disease, and enteritis,including chemotherapy-induced enteritis or radiation-induced enteritis;necrotizing enterocolitis; gastrointestinal injury resulting from toxicinsults such as radiation or chemotherapy; diseases/disorders ofgastrointestinal barrier dysfunction including environmental entericdysfunction, spontaneous bacterial peritonitis; allergy including foodallergy, celiac sprue, and childhood allergy; graft vs. host disease;functional gastrointestinal disorders such as irritable bowel syndrome,functional dyspepsia, functional abdominal bloating/distension,functional diarrhea, functional constipation, and opioid-inducedconstipation; gastroparesis; nausea and vomiting; disorders related tomicrobiome dysbiosis, and other conditions involving the gut-brain axis.In some embodiments, the condition or disorder is a metabolic disorder.In some embodiments, the condition or disorder is type 2 diabetes,hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia,nonalcoholic steatohepatitis, or hypertension. In some embodiments, thecondition or disorder is a nutritional disorder. In some embodiments,the condition or disorder is short bowel syndrome, intestinal failure,or intestinal insufficiency. In some embodiments, the condition ordisorder is inflammatory bowel disease including ulcerative colitis,Crohn's disease and checkpoint inhibitor- induced colitis. In someembodiments, the condition or disorder is celiac disease, enteritisincluding chemotherapy-induced enteritis or radiation-induced enteritis,necrotizing enterocolitis; or gastrointestinal injury resulting fromtoxic insults such as radiation or chemotherapy. In some embodiments,the condition or disorder is diseases/disorders of gastrointestinalbarrier dysfunction including environmental enteric dysfunction,spontaneous bacterial peritonitis; allergy including food allergy,celiac sprue, and childhood allergy; graft vs. host disease; functionalgastrointestinal disorders such as irritable bowel syndrome, functionaldyspepsia, functional abdominal bloating/distension, functionaldiarrhea, functional constipation, opioid-induced constipation;gastroparesis; or nausea and vomiting. In some embodiments, thecondition or disorder is associated with systemic infection andinflammation from having a leaky gut barrier. In some embodiments, thecondition or disorder is metabolic syndrome, obesity, type 2 diabetes,coronary artery disease, fatty liver, nonalcoholic steatohepatitis(NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders includingscleroderma, inflammatory bowel disease including Crohn's disease andulcerative colitis, allergy including food allergy, celiac sprue, andchildhood allergy, graft vs. host disease, irritable bowel syndrome,spontaneous bacterial peritonitis, ischemic colitis, sclerosingcholangitis, Alzheimer's disease, Parkinson's disease, cancer includingcolorectal cancer, depression, autism, or a combination thereof.

Adenosine 5′-Monophosphate-Activated Protein Kinase (AMPK) and the GutBarrier

In some instances, the gut mucosa maintains immune homeostasis underphysiological circumstances by serving as a barrier that restrictsaccess of microbes, diverse microbial products, food antigens and toxinsin the lumen of the gut to rest of the body. In some instances, the gutbarrier is comprised of a single layer of epithelial cells, bound bycell-cell junctions, and a layer of mucin that covers the epithelium. Insome instances, loosening of the junctions induced either by exogenousor endogenous stressors, compromises the gut barrier and allows microbesand antigens to leak through and encounter the host immune system,thereby generating inflammation and systemic endotoxemia. In someinstances, an impaired gut barrier (e.g. a leaky gut) is a majorcontributor to the initiation and/or progression of various chronicdiseases including, but not limited to, metabolic endotoxemia, type 2diabetes, fatty liver disease, obesity, atherosclerosis, inflammatorybowel diseases, and cancers. In some instances, activation of AMPK,which is associated with the maintenance of tight junction in colonicepithelium, controls the progression of colitis. In some instances,expression and assembly of tight junctions is dependent on AMPKactivity.

In some embodiments, the present disclosure provides methods effectiveto strengthen/protect the gut barrier and reduce and/or prevent theprogression of chronic diseases. The gut barrier is a critical frontierthat separates microbes and antigens in the lumen of the gut from therest of the body; a compromised “leaky” gut barrier is frequentlyassociated with systemic infection and inflammation, which is a keycontributor to many chronic allergic, infectious, metabolic andautoimmune diseases such as obesity, diabetes, inflammatory boweldiseases, food allergy, and metabolic endotoxemia.

In some embodiments, this disclosure provides AMPK activators that canbe broadly used for multiple conditions and disorders associated withAMPK. In some embodiments, the condition or disorder is associated withsystemic infection and inflammation from having a leaky gut barrier. Insome embodiments, a leaky gut barrier can fuel the progression ofmultiple chronic diseases, including but not limited to: metabolicsyndrome, obesity, type 2 diabetes, coronary artery disease, fattyliver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepaticencephalopathy, fibrotic disorders including scleroderma, inflammatorybowel disease including Crohn's disease, ulcerative colitis, checkpointinhibitor-induced colitis, allergy including food allergy, celiac sprue,and childhood allergy, graft vs. host disease, irritable bowel syndrome,spontaneous bacterial peritonitis, ischemic colitis, sclerosingcholangitis, Alzheimer's disease, Parkinson's disease, cancer includingcolorectal cancer, depression, autism, or a combination thereof.

In some instances, injury to the intestinal mucosa is frequently adose-limiting complication of radiotherapy and chemotherapy. Approachesto limit the damage to the intestine during radiation and chemotherapyhave been largely ineffective. In some embodiments described herein,AMPK activators are useful for the treatment of gastrointestinal injury.In some embodiments, AMPK activators are useful for the treatment ofgastrointestinal injury resulting from toxic insult. In someembodiments, the toxic insult is from radiation, chemotherapy, or acombination thereof. In some embodiments, the toxic insult isradiation-induced. In some embodiments, the toxic insult ischemotherapy-induced. Gut-Restricted Modulators

In some instances, there are concerns associated with systemic AMPKactivation, for example, AMPK activation in the heart. For example, insome instances, activating mutations in the AMPK γ2-subunit lead toPRKAG2 cardiomyopathy. In other instances, systemic AMPK activationresults in cardiac hypertrophy and increased cardiac glycogen. In someinstances, given the potential association of adverse effects withsystemic AMPK activation, tissue selective AMPK activation is anattractive approach for developing AMPK activators to treat disease.

In some embodiments, the AMPK activator is gut-restricted. In someembodiments, the AMPK activator is designed to be substantiallynon-permeable or substantially non-bioavailable in the blood stream. Insome embodiments, the AMPK activator is designed to activate AMPKactivity in the gut and is substantially non-systemic. In someembodiments, the AMPK activator has low systemic exposure.

In some embodiments, a gut-restricted AMPK activator has low oralbioavailability. In some embodiments, a gut-restricted AMPK activatorhas <40% oral bioavailability, <30% oral bioavailability, <20% oralbioavailability, <10% oral bioavailability, <8% oral bioavailability,<5% oral bioavailability, <3% oral bioavailability, or <2% oralbioavailability.

In some embodiments, the unbound plasma levels of a gut-restricted AMPKactivator are lower than the EC₅₀ value of the AMPK activator againstAMPK. In some embodiments, the unbound plasma levels of a gut-restrictedAMPK activator are significantly lower than the EC₅₀ value of thegut-restricted AMPK activator against AMPK. In some embodiments, theunbound plasma levels of the AMPK activator are 2-fold, 10-fold,20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the EC₅₀value of the gut-restricted AMPK activator against AMPK.

In some embodiments, a gut-restricted AMPK activator has low systemicexposure. In some embodiments, the systemic exposure of a gut-restrictedAMPK activator is, for example, less than 500, less than 200, less than100, less than 50, less than 20, less than 10, or less than 5 nM, boundor unbound, in blood serum. In some embodiments, the systemic exposureof a gut-restricted AMPK activator is, for example, less than 500, lessthan 200, less than 100, less than 50, less than 20, less than 10, orless than 5 ng/mL, bound or unbound, in blood serum.

In some embodiments, a gut-restricted AMPK activator has high intestinalexposure. In some embodiments, the intestinal exposure of agut-restricted AMPK activator is, for example, greater than 1, 5, 10,50, 100, 250 or 500 μM.

In some embodiments, a gut-restricted AMPK activator has high exposurein the colon.

In some embodiments, the colon exposure of a gut-restricted AMPKactivator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500μM. In some embodiments, the colon exposure of a gut-restricted AMPKactivator is, for example, greater than 100 μM.

In some embodiments, a gut-restricted AMPK activator has lowpermeability. In some embodiments, a gut-restricted AMPK activator haslow intestinal permeability. In some embodiments, the permeability of agut-restricted AMPK activator is, for example, less than 5.0×10⁻⁶ cm/s,less than 2.0×10⁻⁶ cm/s, less than 1.5×10⁻⁶ cm/s, less than 1.0×10⁻⁶cm/s, less than 0.75×10⁻⁶ cm/s, less than 0.50×10⁻⁶ cm/s, less than0.25×10⁻⁶ cm/s, less than 0.10×10⁻⁶ cm/s, or less than 0.05 ×10⁻⁶ cm/s.

In some embodiments, a gut-restricted AMPK activator has low absorption.In some embodiments, the absorption of a gut-restricted AMPK activatoris less than 40%, less than 30%, less than 20%, less than 10%, less than5%, or less than 1%.

In some embodiments, a gut-restricted AMPK activator has high plasmaclearance. In some embodiments, a gut-restricted AMPK activator isundetectable in plasma in less than 8 hours, less than 6 hours, lessthan 4 hours, less than 3 hours, less than 120 min, less than 90 min,less than 60 min, less than 45 min, less than 30 min, or less than 15min.

In some embodiments, a gut-restricted AMPK activator is rapidlymetabolized upon administration. In some embodiments, a gut-restrictedAMPK activator has a short half-life. In some embodiments, the half-lifeof a gut-restricted AMPK activator is less than less than 8 hours, lessthan 6 hours, less than 4 hours, less than 3 hours, less than 120 min,less than 90 min, less than 60 min, less than 45 min, less than 30 min,or less than 15 min. In some embodiments, the metabolites of agut-restricted AMPK activator have rapid clearance. In some embodiments,the metabolites of a gut- restricted AMPK activator are undetectable inless than 8 hours, less than 6 hours, less than 4 hours, less than 3hours, less than 120 min, less than 90 min, less than 60 min, less than45 min, less than 30 min, or less than 15 min. In some embodiments, themetabolites of a gut-restricted AMPK activator have low bioactivity. Insome embodiments, the EC₅₀ value of the metabolites of a gut- restrictedAMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold,500-fold, or 1000- fold higher than the EC₅₀ value of the gut-restrictedAMPK activator against AMPK. In some embodiments, the metabolites of agut-restricted AMPK activator have rapid clearance and low bioactivity.

In some embodiments, the gut-restricted AMPK activator has high efflux.In some embodiments, the gut-restricted AMPK activator is a substratefor one or more intestinal efflux transporters such as P-gp (MDR1),BCRP, or MRP2. In some embodiments, the efflux of the gut-restrictedAMPK activator as measured by the B-A/A-B ratio in a cell line such asCaco-2 or MDCK with or without over-expression of one or more effluxtransporters is, for example, greater than 2, greater than 5, greaterthan 10, greater than 25, or greater than 50.

In some embodiments of the methods described herein, the AMPK activatoris gut-restricted. In some embodiments, the AMPK activator is agut-restricted AMPK agonist. In some embodiments, the AMPK activator isa gut-restricted AMPK super agonist. In some embodiments, the AMPKactivator is a gut-restricted AMPK full agonist. In some embodiments,the AMPK activator is a gut-restricted AMPK partial agonist. In someembodiments, the AMPK activator is covalently bonded to a kinetophore.In some embodiments, the AMPK activator is covalently bonded to akinetophore through a linker.

Compounds

Disclosed herein, in some embodiments, is a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein:

X is —O—, —S—, —NR³—, —C(O)—, —C(O)O—**, —C(O)NR³—**, —NR³C(O)—**,—SO₂—, or —SO₂NR³—**; wherein ** indicates the attachment point to G;

Y is N, CH, or CR²;

G is C₁-C₅ alkyl, —(CH₂)_(j)-(C₃-C₁₀ cycloalkyl), —(CH₂)_(j)-(C₄-locycloalkenyl), —(CH₂)_(j)-(aryl), —(CH₂)_(j)-(heteroaryl),—(CH₂)_(j)-(3- to 10-membered heterocycloalkyl), or —(CH₂)_(j)-(5- to10-membered heterocycloalkenyl), which is substituted with 1, 2, 3, or 4substituents selected from —(CH₂)_(h)-C(O)OR⁷, —(CH₂)_(h)—P(O)(R⁷)OR⁷,—(CH₂)_(h)—P(O)(OR⁷)₂, —(CH₂)_(h)—S(O)₂OR⁷, -and —(CH₂)_(h)OH; and isfurther optionally substituted with 1, 2, 3, or 4 substituents selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆fluoroalkyl, —O—(C₁-C₆ alkyl), ═O and ═S;

is aryl, heteroaryl, —C≡C—, or absent; wherein if

is —C≡C—or absent, then p is 0;

is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C₅₋₁₀ cycloalkenyl,or 5- to 10-membered heterocycloalkenyl;

D is K, -Z-NR⁵R⁶, or R^(c);

Z is —(CH₂)_(r)—, —(CH(CH₃)—, *—(CH₂)_(r)-C(═O)—, or*—(CH₂)_(r)—S(═O)₂—, where * represents

attachment to

K is —SO₂OH, —S(O)OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —B(OR^(d))(OH), —NHC(O)H,—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)),—NHC(O)NH(R^(d)), —N(R^(d))C(═N(R^(d))N(R^(d))₂,—N(R^(d))C(═NH)NHC(═NH)NH₂,

each R^(a) and R^(b) is independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)R¹³, —C(O)OR¹⁴, —OC(O)R¹³, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴, —NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroarylare unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;

R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl,C₁₋₁₀ alkoxyl, or _([(C(R) ^(d))₂)_(s)—V]_(t)—R⁹; wherein each V isindependently —C(R^(d))₂O₂—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and alkoxyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺, K,and -Z-NR⁵R⁶; or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andalkoxyl is substituted by 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂;

each R^(d) is independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl;wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3halogen or —OH groups;

each R^(e) is independently C₁₋₅ alkyl or C₃₋₆ cycloalkyl; wherein thealkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or—OH groups;

R^(t) is hydrogen or C₁-C₄ alkyl;

each R² is independently halogen, —CN, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl,or C₃-C₆ cycloalkyl;

R³ is hydrogen or C₁-C₄ alkyl;

R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups;

or R⁵ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃-10 cycloalkyl,C₅-lo cycloalkenyl, 3- to 8-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl; wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or whereinthe alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,or heterocycloalkenyl is substituted by 2-6 groups selected from —CO₂H,—OH, and —N(R^(d))₂; and wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl isoptionally further substituted by 1, 2, or 3 R^(f) groups;

each R^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)R¹³, —C(O)OR¹⁴, —OC(O)R¹³, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴, —NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, 4- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroarylare unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;

or R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—;

or R⁵ is —(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl;wherein the aryl or heteroaryl is substituted by 1-6 groups selectedfrom —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein thealkylene is unsubstituted or substituted by 1, 2, or 3 E^(f groups;)

R⁶ is hydrogen, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; wherein the alkyl andcycloalkyl are unsubstituted or substituted by 1-3 groups independentlyselected from halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)R¹³, —C(O)OR¹⁴,—OC(O)R¹³, —C(O)NR¹⁴R¹⁴, NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴,NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, or —P(O)(OR¹⁴)₂;

or R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 1-6 groups selected from —CH₃, —CH₂OH,—CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺ and K; or with 2-6groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂;

each R⁷ is independently hydrogen or C₁-C₄ alkyl;

R⁹ is hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₈ cycloalkyl,C₅₋₈ cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl,monocyclic heteroaryl, or bicyclic heteroaryl, wherein the alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl phenyl,naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl is unsubstitutedor substituted by 1-6 groups selected from —OH, —CO₂H, —N(R^(e))₂,—N(R^(e))₃ ⁺, and K;

each R^(—)is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-membered heterocycloalkyl,phenyl, or monocyclic heteroaryl; and

each R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl;

or two R¹⁴ on the same nitrogen atom are taken together with thenitrogen to which they are attached to form a 3- to 6-memberedN-heterocycloalkyl;

each h is independently 0-4;

j is 0-4;

n is 0-2;

p is 0-3;

q is 0-3;

r is 0-3;

each s is independently 1-6; and

each t is independently 1-6.

For any and all of the embodiments, substituents are selected from amonga subset of the listed alternatives. For example, in some embodiments, Yis N, CH, or CR². In some embodiments, Y is N or CH. In someembodiments, Y is N. In some embodiments, Y is CH. In some embodiments,Y is CR².

In some embodiments, n is 0-1. In some embodiments, n is 1-2. In someembodiments, n is 0. In some embodiments, n is 1. In some embodiments, nis 2.

In some embodiments, R¹ is methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl, or tert-butyl. In some embodiments, R¹ is methyl,ethyl, or i-propyl. In some embodiments, R¹ is hydrogen or methyl. Insome embodiments, R¹ is hydrogen. In some embodiments, R¹ is methyl.

In some embodiments, each R² is independently halogen, —CN, C₁-C₄ alkyl,or C₁-C₄ fluoroalkyl. In some embodiments, each R² is independently —F,—Cl, —CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, —CH₂F, —CHF2, or —CF₃. In some embodiments, eachR² is independently —F, —Cl, —CN, methyl, ethyl, isopropyl, or —CF₃. Insome embodiments, each R² is independently —F, —Cl, or —CN. In someembodiments, each R² is independently —Cl.

In some embodiments, Y is N or CH; R¹⁴ is hydrogen or methyl; and eachR² is independently —F, —Cl, —CN, methyl, ethyl, isopropyl, or —CF₃. Insome embodiments, Y is N; R¹ is hydrogen; R² is —F, —Cl, or —CN; and nis 1. In some embodiments, Y is N or CH; R¹⁴ is hydrogen; R² is —Cl; andn is 1. In some embodiments, Y is N; R¹⁴ is hydrogen; R² is —Cl; and nis 1. In some embodiments, Y is CH; R¹⁴ is hydrogen; R² is —Cl; and n is1.

In some embodiments,

is aryl, heteroaryl, —C≡C—, or absent. In some

embodiments,

is —C≡C- and p is 0. In some embodiments,

is absent and p is 0.

In some embodiments,

is aryl or heteroaryl. In some embodiments,

is aryl. In some embodiments,

is heteroaryl. In some embodiments,

is phenyl or 5- or 6-membered monocyclic heteroaryl. In someembodiments,

is phenyl or 6-membered monocyclic heteroaryl. In some embodiments,

is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, orthiadiazolyl. In some embodiments,

is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In someembodiments,

is phenyl or pyridinyl. In some embodiments,

is phenyl.

In some embodiments,

is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C₅₋₁₀ cycloalkenyl,or 5- to 10-membered heterocycloalkenyl. In some embodiments,

is aryl, heteroaryl, C₃-C₆ cycloalkyl, 3- to 8-memberedheterocycloalkyl, or 5- to 10-membered bicyclic heterocycloalkenyl. Insome embodiments,

is phenyl, 5- or 6-membered monocyclic heteroaryl, C₃-C₆ cycloalkyl, 3-to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl.In some embodiments,

is phenyl, C₃-C₆ cycloalkyl, or 3- to 8-membered heterocycloalkyl.

In some embodiments,

is aryl or heteroaryl. In some embodiments,

is phenyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-memberedbicyclic heteroaryl. In some

embodiments,

is phenyl or 5- or 6-membered monocyclic heteroaryl. In someembodiments,

is phenyl or 6-membered monocyclic heteroaryl. In some embodiments,

is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, orthiadiazolyl. In some embodiments,

is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In someembodiments,

is phenyl or pyridinyl. In some embodiments,

is phenyl.

In some embodiments,

is cycloalkyl, heterocycloalkyl, C₅₋₁₀ cycloalkenyl, or 5- to10-membered heterocycloalkenyl. In some embodiments,

is C₃-C₆ cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to10-membered bicyclic heterocycloalkenyl. In some embodiments,

is C₃-C₆ cycloalkyl or 3- to 8-membered heterocycloalkyl.

In some embodiments,

is aryl or heteroaryl; and

is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C₅₋₁₀ cycloalkenyl,or 5- to 10-membered heterocycloalkenyl. In some

embodiments,

is phenyl or 5- or 6-membered monocyclic heteroaryl; and

is phenyl, 5- or 6-membered monocyclic heteroaryl, C₃-C₆ cycloalkyl, 3-to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl.In some embodiments,

is phenyl and

is phenyl.

In some embodiments,

is —C≡C-; p is 0; and

and is phenyl or 5- or 6-membered monocyclic heteroaryl. In otherembodiments,

is absent; p is 0; and

is phenyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-memberedbicyclic heteroaryl.

In some embodiments, the compound has the structure of Formula (II):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof. In some embodiments of a compound of Formula (II),

is phenyl, C₃-C₆ cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to10-membered bicyclic heterocycloalkenyl. In some embodiments of acompound of Formula (II),

is phenyl, C₃-C₆ cycloalkyl, or 3- to 8-membered heterocycloalkyl. Insome embodiments of a compound of Formula (II),

is phenyl.

In some embodiments, the compound has the structure of Formula (III):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.

In some embodiments, each R³ is independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, l C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl.In some embodiments, each R^(a) is independently —F, —Cl, —CN, —OH,—O-(C₁-C₆ alkyl), C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl. In someembodiments, each R^(a) is independently —F, —Cl, —CN, —OH, —OCH₃,—OCF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, —CH₂F, —CHF2, or —CF₃. In some embodiments, each R^(a) isindependently —F, —Cl, —CN, —OH, —OCH₃, —OCF₃, methyl, or —CF_(3.)

In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0, 1,or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 0. Insome embodiments, p is 1, 2, or 3.

In some embodiments, each R^(b) is independently halogen, —CN, —OH,—OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, or C₁-C₆fluoroalkyl. In some embodiments, each R^(b) is independently —F, —Cl,—CN, —OH, —O-(C₁-C₆ alkyl), C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl. In someembodiments, each R^(b) is independently —F, —Cl, —CN, —OH, —OCH₃,—OCF₃, methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, —CH₂F, —CHF₂, or —CF₃. In some embodiments, each R^(b) isindependently —F, —Cl, —CN, —OH, —OCH—₃, —OCF₃, methyl, or —CF₃. In someembodiments, each R^(b) is independently —OH.

In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1,or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 0. Insome embodiments, q is 1, 2, or 3.

In some embodiments, each R^(a) and R^(b) is independently halogen, —CN,—OH, —OR¹³, —NR¹⁴R¹⁴, C(O)OR¹⁴, C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, or C₁-C₆fluoroalkyl; p is 0 or 1; and q is 0 or 1. In some embodiments, eachR^(a)and R^(b) is independently —F, —Cl, —CN, —OH, —OCH₃, —OCF₃, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl,—CH₂F, —CHF₂, or —CF₃; p is 0 or 1; and q is 0 or 1. In someembodiments, each R^(a) and R^(b) is independently —F, —Cl, —CN, —OH,—OCH₃, —OCF₃, methyl, or —CF₃; p is 0 or 1; and q is 0 or 1. In someembodiments, p is 0; q is 1, and R^(b) is —OH. In some embodiments, p is0; and q is 0.

In some embodiments, the compound has the structure of Formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.

In some embodiments,

is —C≡C-; p is 0; and

is phenyl or 5- or 6-membered monocyclic heteroaryl. In otherembodiments,

is absent; p is 0; and

is phenyl, 5- or 6-membered monocyclic heteroaryl, or 8- to 10-memberedbicyclic heteroaryl.

In some embodiments, X is —O—, —S—, —NR³—, —C(O)NR³—**, —NR³C(O)—**, or—SO₂NR³—**; wherein ** indicates the attachment point to G. In someembodiments, X is —O—, —S—, or —NR³—. In some embodiments, X is —O—or—S—. In some embodiments, X is —O—. In some embodiments, X is —S—. Insome embodiments, X is —NR³—. In some embodiments, X is —C(O)NR³—**;wherein ** indicates the attachment point to G. In some embodiments, Xis —NR³C(O)—**; wherein ** indicates the attachment point to G. In someembodiments, X is —SO₂NR³—**; wherein ** indicates the attachment pointto G.

In some embodiments, R³ is hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, sec-butyl, or tert-butyl. In some embodiments, R³ ishydrogen, methyl, ethyl, or i-propyl. In some embodiments, R³ ishydrogen or methyl. In some embodiments, R³ is hydrogen. In someembodiments, R³ is methyl.

In some embodiments, X is —O—, —S—, —NR³—, —C(O)NR³—**, —NR³C(O)—**, or—SO₂NR³—**; wherein ** indicates the attachment point to G; and R³ ishydrogen or methyl. In some embodiments, X is —O—or —S—. In someembodiments, X is —O—.

In some embodiments, G is C₁-C₅ alkyl, C₃-C₁₀ cycloalkyl, —CH₂-(C₃-C₁₀cycloalkyl), aryl, 3- to 10-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4substituents selected from —(CH₂)_(h)—C(O)OR⁷, —(CH₂)_(h)—P(O)(R⁷)OR⁷,—(CH₂)_(h)—P(O)(OR⁷)₂, —(CH₂)_(h)—S(O)₂OR⁷, —and —(CH₂)_(h)OH; and isfurther optionally substituted with 1, 2, 3, or 4 substituents selectedfrom C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆fluoroalkyl, and —O-(C₁-C₆ alkyl); each R⁷ is independently hydrogen,methyl, or ethyl; and his 0-1.

In some embodiments, G is C₁-C₅ alkyl, C₃-C₁₀ cycloalkyl, —CH₂-(C₃-C₁₀cycloalkyl), aryl, 3- to 10-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂,—S(O)₂OH, —OH, and —CH₂OH; and is further optionally substituted with 1,2, 3, or 4 substituents selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆ hydroxyalkyl, C₁-C₆ fluoroalkyl, and —O-(C₁-C₆ alkyl).

In some embodiments, G is C₁-C₅ alkyl, C₃-C₁₀ cycloalkyl, —CH₂-(C₃-C₁₀cycloalkyl), aryl, 3- to 10-membered heterocycloalkyl, or 5- to10-membered heterocycloalkenyl, which is substituted with 1 or 2substituents selected from —C(O)OH, —OH, and —CH₂OH; and is furtheroptionally substituted with 1 or 2 substituents selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ fluoroalkyl, and —O-(C₁-C₆ alkyl).

In some embodiments, G is 3- to 10-membered heterocycloalkyl, which issubstituted with 1, 2, 3, or 4 substituents selected from —C(O)OH,—CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH. In someembodiments, G is 3- to 10-membered heterocycloalkyl, which issubstituted with 1 or 2 substituents selected from —C(O)OH, —CH₂C(O)OH,—P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH. In some embodiments,G is 3- to 10-membered heterocycloalkyl, which is substituted with 1 or2 substituents selected from —C(O)OH, —OH, and —CH₂OH. In someembodiments, G is 3- to 10-membered heterocycloalkyl, which issubstituted with 1 or 2 substituents selected from —OH and —CH₂OH.

In some embodiments, G is monocyclic 3- to 6-membered heterocycloalkylcontaining 1 oxygen atom, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH; or G is bicyclic 8- to 10-membered heterocycloalkylcontaining 2 oxygen atoms, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH.

In some embodiments, G is monocyclic 3- to 6-membered heterocycloalkylcontaining 1 oxygen atom, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is monocyclic 3- to 6-memberedheterocycloalkyl containing 1 oxygen atom, which is substituted with 1or 2 substituents selected from —C(O)OH, —OH, and —CH₂OH.

In some embodiments, G is bicyclic 8- to 10-membered heterocycloalkylcontaining 2 oxygen atoms, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is bicyclic 8- to 10-memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1or 2 substituents selected from —C(O)OH, —OH, and —CH₂OH. In someembodiments, G is bicyclic 8- to 10-membered heterocycloalkyl containing2 oxygen atoms, which is substituted with 1 or 2 substituents selectedfrom —OH and —CH₂OH. In some embodiments, G is bicyclic 8- to10-membered heterocycloalkyl containing 2 oxygen atoms, which issubstituted with 1 substituent selected from —OH and —CH₂OH. In someembodiments, G is bicyclic 8- to 10-membered heterocycloalkyl containing2 oxygen atoms, which is substituted with 1 —OH substituent.

In some embodiments, G is C₁-C₅ alkyl, C₃-C₆ cycloalkyl, —CH₂—(C₃-C₆cycloalkyl), or phenyl, which is substituted with 1, 2, 3, or 4substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂,—S(O)₂OH, —OH, and —CH₂OH; and is further optionally substituted with 1or 2 substituents selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆hydroxyalkyl. In some embodiments, G is C₁-C₅ alkyl, C₃-C₆ cycloalkyl,—CH₂-(C₃-C₆ cycloalkyl), or phenyl, which is substituted with 1 or 2substituents selected from —C(O)OH, —OH, and —CH₂OH; and is furtheroptionally substituted with 1 or 2 substituents selected from C₁-C₆alkyl and C₁-C₆ hydroxyalkyl.

In some embodiments, -X-G is selected from:

In some embodiments, -X-G is selected from:

In some embodiments, -X-G is:

In some embodiments, -X-G is:

In some embodiments, -X-G is:

In some embodiments, -X-G is:

In some embodiments, D is R^(c). In some embodiments, D is R^(c); andR^(c) is substituted by K. In some embodiments, D is R^(c); and R^(c) issubstituted by -Z-NR⁵R⁶.

In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₁₀ alkoxyl, or—[(C(R^(d))₂)_(s)-V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and alkoxyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺, K,and -Z-NR⁵R⁶. In some embodiments, D is R^(c); _(and R) ^(c) is C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl; wherein thealkyl, alkenyl, alkynyl, or alkoxyl is substituted by 1-6 groupsselected from —N(R^(e))₃ ⁺, K, and -Z-NR⁵R⁶. In some embodiments, D isR^(c); and R^(C) is C₁₋₁₀ alkyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl;wherein the alkyl, alkynyl, or alkoxyl is substituted by 1-3 groupsselected from —N(R^(e))₃ ⁺, K, and -Z-NR⁵R⁶. In some embodiments, D isR^(c); and R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl;wherein the alkyl, alkynyl, or alkoxyl is substituted by 1 groupselected from —N(R^(e))₃ ⁺, K, and -Z-NR⁵R⁶. In some embodiments, eachRe i_(s) independently C₁₋₆ alkyl. In some embodiments, D is R^(c); andR^(c) is C₁₋₁₀ alkyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl; wherein thealkyl, alkynyl, or alkoxyl is substituted by 1 group selected from—N(R^(e))₃ ⁺, K, and -Z-NR⁵R⁶; and each R^(e) is independently C₁₋₆alkyl. In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀alkynyl, or C₁₋₁₀ alkoxyl; wherein the alkyl, alkynyl, or alkoxyl issubstituted by K. In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀alkyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl; wherein the alkyl, alkynyl, oralkoxyl is substituted by -Z-NR⁵R⁶.

In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ cycloalkyl, C₁₋₁₀ alkoxyl, or—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and alkoxyl is substituted by 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂. In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl; wherein the alkyl,alkenyl, alkynyl, or alkoxyl is substituted by 2-6 groups selected from—CO₂H, —OH, and —N(R^(d))₂. In some embodiments, D is R^(c); and R^(c)is C₁₋₁₀ alkyl, C₂₋₁₀ alkynyl, or C₁₋₁₀ alkoxyl; wherein the alkyl,alkynyl, or alkoxyl is substituted by 4-6 groups selected from —CO₂H,—OH, and —N(R^(d))₂. In some embodiments, D is R^(c); and R^(c) is C₁₋₁₀alkyl, C₂₋₁₀alkynyl, or C₁₋₁₀ alkoxyl; wherein the alkyl, alkynyl, oralkoxyl is substituted by 5 —OH groups.

In some embodiments, D is R^(c); and R^(c) is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂,—N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—, —C(R^(d))₂SO₂—, or—C(R^(d))₂S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and alkoxyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺, K,and -Z-NR⁵R⁶; or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, andalkoxyl is substituted by 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂. In some embodiments, D is R^(c); and R^(c) is—[(C(R^(d))₂)_(s)-V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, or —C(R^(d))₂N⁺(R^(d))₂-; and whereineach alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by1-6 groups selected from —N(R^(e))₃ ⁺, K, and -Z- NR⁵R⁶; or wherein eachalkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by 2-6groups selected from —CO₂H, —OH, and —N(R^(d))₂.

In some embodiments, D is K or -Z-NR⁵R⁶.

In some embodiments, D is K; or D is Re; wherein R^(c) is substituted byK. In some embodiments, D is K. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)), —

NHC(O)NH(R^(d)), In some embodiments,

K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—N(R^(d))C(O)NHSO₂(R^(d)), —

C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)), —NHC(O)NH(R^(d)), In someembodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)). In someembodiments, each R^(d) is independently hydrogen or C₁₋₆ alkyl. In someembodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and eachR^(d) is independently hydrogen or C₁₋₆ alkyl. In some embodiments, K is—SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₃ alkyl. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or methyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, - P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or - P(O)(OH)₂. In some embodiments, K is—SO₂OH. In some embodiments, K is —P(O)(OH)₂.

In some embodiments, D is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and eachR^(d) is independently hydrogen or C₁₋₆ alkyl. In some embodiments, D is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, - P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe). In some embodiments, D is —SO₂OH or - P(O)(OH)₂. In someembodiments, D is —SO₂OH. In some embodiments, D is —P(O)(OH)₂.

In some embodiments, D is -Z-NR⁵R⁶; or D is Re; wherein R^(c) issubstituted by -Z-NR⁵R⁶. In some embodiments, D is -Z-NR⁵R⁶.

In some embodiments, Z is —(CH₂)_(r)—, *—(CH₂)_(r)—C(═O)—, or*—(CH₂)_(r)—S(═O)₂—, where *

represents attachment to

In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0or 1. In some embodiments, r is 0. In some embodiments, r is 1. In someembodiments, Z is —(CH₂)—, —C(═O)—, *—(CH₂)—C(═O)—, —S(═O)₂—, or*—(CH₂)—S(═O)₂—. In some embodiments, Z is —(CH₂)—, —(CH(CH₃)—, —C(═O)—,or —S(═O)₂—. In some embodiments, Z is —(CH₂)—, —C(═O)—, or —S(═O)₂—. Insome embodiments, Z is —(CH₂)—. In some embodiments, Z is —(CH(CH₃)—. Insome embodiments, Z is —C(═O)—or —S(═O)₂—. In some embodiments, Z is—C(═O)—. In some embodiments, Z is —S(═O)₂—.

In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9—OH groups. In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substitutedby 5 —OH groups.

In some embodiments, R⁵ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ cycloalkyl, C₅₋₁₀ cycloalkenyl, 3- to 8-membered heterocycloalkyl,or 5- to 10-membered heterocycloalkenyl; wherein the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl is substituted by 1-6 groups selected from —N(R^(e))₃⁺ and K; or wherein the alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted by2-6 groups selected from —CO₂H, —OH, and —N(R^(d))₂; and wherein thealkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, orheterocycloalkenyl is optionally further substituted by 1, 2, or 3 R^(f)groups. In some embodiments, R⁵ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, or C₃₋₁₀ cycloalkyl wherein the alkyl, alkenyl, alkynyl, orcycloalkyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺ andK; and the alkyl, alkenyl, alkynyl, or cycloalkyl is optionally furthersubstituted by 1, 2, or 3 R^(f) groups. In some embodiments, R⁵ is C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, or C₂₋₁₀ alkynyl; wherein the alkyl, alkenyl, oralkynyl is substituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K;and the alkyl, alkenyl, or alkynyl is optionally further substituted by1, 2, or 3 R^(f) groups. In some embodiments, R⁵ is C₁₋₁₀ alkyl or C₂₋₁₀alkynyl; wherein the alkyl or alkynyl is substituted by 1-3 groupsselected from —N(R^(e))₃ ⁺ and K; and the alkyl or alkynyl is optionallyfurther substituted by 1, 2, or 3 R^(f) groups. In some embodiments, R⁵is C₁₋₁₀ alkyl or C₂₋₁₀ alkynyl; wherein the alkyl or alkynyl issubstituted by 1 group selected from —N(R^(e))₃ ⁺ and K; and the alkylor alkynyl is optionally further substituted by 1, 2, or 3 R^(f) groups.In some embodiments, each R^(e) is independently C₁₋₆ alkyl. In someembodiments, R⁵ is C₁₋₁₀ alkyl or C₂₋₁₀ alkynyl; wherein the alkyl, oralkynyl is substituted by 1 group selected from —N(R^(e))₃ ⁺ and K; andthe alkyl or alkynyl is optionally further substituted by 1, 2, or 3R^(f) groups; and each Re is independently C₁₋₆ alkyl. In someembodiments, R⁵ is C₁₋₁₀ alkyl or C₂₋₁₀ alkynyl; wherein the alkyl oralkynyl is substituted by K; and the alkyl or alkynyl is optionallyfurther substituted by 1, 2, or 3 R^(f) groups. In some embodiments, R⁵is C₁₋₁₀ alkyl which is substituted by 1-6 groups selected from—N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂; and is optionally further substituted by 1, 2, or 3 R^(f)groups.

In some embodiments, R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each Vis independently - C(R^(d))₂O—, —C(R^(d))₂NR^(d)—,—C(R^(d))₂N⁺(R^(d))₂—, —N(R^(d))—C(O)—N(R^(d))—, —C(O)N(R^(d))—,—C(R^(d))₂SO₂—, or —C(R^(d))₂S(O)—. In some embodiments, R⁵ is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently -C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —C(R^(d))₂N⁺(R^(d))₂—,—N(R^(d))—C(O)—N(R^(d))—, or —C(O)N(R^(d))—. In some embodiments, R⁵ is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)-, —C(R^(d))₂N⁺(R^(d))₂—, or—N(R^(d))—C(O)—N(R^(d))—. In some embodiments, R⁵ is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, or —N(R^(d))—C(O)—N(R^(d))—, or—C(O)N(R^(d))—. In some embodiments, R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹;wherein each V is independently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, or—N(R^(d))—C(O)—N(R^(d))—. In some embodiments, R⁵ is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—. In some embodiments, each R^(d) is independently hydrogenor C₁₋₆ alkyl. In some embodiments, R⁹ is hydrogen, C₁₋₈ alkyl, phenyl,or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted orsubstituted by 1-6 groups selected from —OH, —CO₂H, —N(R^(e))₂,—N(R^(e))₃ ⁺, and K. In some embodiments, R⁹ is hydrogen. In someembodiments, R⁹ is C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl,phenyl, or naphthyl is unsubstituted or substituted by 1-3 groupsselected from —OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K. In someembodiments, R⁹ is naphthyl, which is unsubstituted or substituted by 1group selected from K.

In some embodiments, R⁵ is —(C₁-C₆ alkylene)—aryl, or —(C₁-C₆alkylene)—heteroaryl; wherein the aryl or heteroaryl is substituted by1-6 groups selected from —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K;and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3R^(f) groups. In some embodiments, R⁵ is —(C₁-C₄ alkylene)—aryl, or—(C₁-C₄ alkylene)—heteroaryl; wherein the aryl or heteroaryl issubstituted by 1-6 groups selected from —CO₂H, —OH, —N(R^(d))₂,—N(R^(e))₃ ⁺, and K; and wherein the alkylene is unsubstituted orsubstituted by 1, 2, or 3 R^(f) groups. In some embodiments, R⁵ is—(C₁-C₄ alkylene)—aryl, or —(C₁-C₄ alkylene)—heteroaryl; wherein thearyl or heteroaryl is substituted by 1-6 groups selected from —CO₂H,—OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein the alkylene isunsubstituted. In some embodiments, the aryl is selected from phenyl andnaphthyl. In some embodiments, the heteroaryl is selected frommonocyclic or bicyclic heteroaryl.

In some embodiments, R⁵ and R⁶ are taken together with the nitrogen towhich they are attached to form a 3- to 6-membered N-heterocycloalkylwhich is unsubstituted or substituted with 1-6 groups selected from—CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺ and

K; or with 2-6 groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂,—CH₂CH₂OH, —CH₂OCH₂CH₂OH, and —N(R^(d))₂. In some embodiments, R⁵ and R⁶are taken together with the nitrogen to which they are attached to forma 3- to 6-membered N-heterocycloalkyl which is unsubstituted orsubstituted with 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with2-6 groups selected from —CO₂H, —OH, —CH₂OH, and —N(R^(d))₂. In someembodiments, R⁵ and R⁶ are taken together with the nitrogen to whichthey are attached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 2-6 groups selected from —CO₂H, —OH,—CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, and —N(R^(d))₂. In someembodiments, R⁵ and R⁶ are taken together with the nitrogen to whichthey are attached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 2-6 groups selected from —CO₂H, —OH,—CH₂OH, and —N(R^(d))₂. In some embodiments, R⁵ and R⁶ are takentogether with the nitrogen to which they are attached to form a 3- to6-membered N-heterocycloalkyl which is unsubstituted or substituted with2-4 groups selected from —OH and —CH₂OH. In some embodiments, R⁵ and R⁶are taken together with the nitrogen to which they are attached to forma 4- to 6-membered N-heterocycloalkyl which is unsubstituted orsubstituted with 2-4 groups selected from —OH and —CH₂OH. In someembodiments, R⁵ and R⁶ are taken together with the nitrogen to whichthey are attached to form a 4- to 6-membered N-heterocycloalkyl which issubstituted with 2-4 groups selected from —OH and —CH₂OH.

In some embodiments, each R^(f) is independently halogen, —CN, —OH,—OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)NR¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl, wherein thealkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2,or 3 halogen or —OH groups. In some embodiments, each R^(f) isindependently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴R¹⁴, C₃-C₆cycloalkyl, or phenyl, wherein the cycloalkyl, or phenyl, isunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups. Insome embodiments, each R^(f) is —OH.

In some embodiments, R⁶ is hydrogen or C₁₋₆ alkyl; wherein the alkyl isunsubstituted or substituted by 1-3 groups independently selected fromhalogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)R¹³, —C(O)OR¹⁴, —OC(O)_(R) ¹³,—C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, —OC(O)NR¹⁴R¹⁴,—NR¹⁴C(O)OR¹⁴, —OC(O)OR¹⁴, or —P(O)(OR¹⁴)₂. In some embodiments, R⁶ ishydrogen or C₁₋₆ alkyl; wherein the alkyl is unsubstituted orsubstituted by 1-3 groups independently selected from halogen, —CN, —OH,—OR¹³, —NR¹⁴R¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, or—P(O)(OR¹⁴)₂. In some embodiments, R⁶ is hydrogen or C₁₋₆ alkyl; whereinthe alkyl is unsubstituted or substituted by 1-3 groups independentlyselected from halogen, —OH, or —C(O)NR¹⁴R¹⁴. In some embodiments, R⁶ ishydrogen or C₁₋₆ alkyl; wherein the alkyl is unsubstituted orsubstituted by 1-3 halogen or —OH groups. In some embodiments, R⁶ ishydrogen or C₁₋₆ alkyl; wherein the alkyl is unsubstituted orsubstituted by 1-3 —OH groups. In some embodiments, R⁶ is hydrogen orC₁₋₆ alkyl. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶is C₁₋₆ alkyl.

In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9—OH group and R⁶ is hydrogen or C₁₋₆ alkyl. In some embodiments, R⁵ isC₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups and R⁶ is C₁₋₆alkyl. In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5to 9 —OH groups and R⁶ is hydrogen. In some embodiments, R⁵ is C₆-C₁₀alkyl that is substituted by 5 —OH groups and R⁶ is hydrogen.

In some embodiments, R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6 groups selectedfrom —CO₂H, —OH, and —N(R^(d))₂; and is optionally further substitutedby 1, 2, or 3 R^(f) groups; each R^(f) is independently halogen, —CN,—OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl, wherein thealkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2,or 3 halogen or —OH groups; and R⁶ is hydrogen or C₁₋₆ alkyl, which isunsubstituted or substituted by 1-3 groups independently selected fromhalogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴,—NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, or —P(O)(OR¹⁴)₂. In some embodiments, R⁵is C₁₋₁₀ alkyl which is substituted by 1-6 groups selected from—N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂; and is optionally further substituted by 1, 2, or 3 R^(f)groups; each R^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl,is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups; andR⁶ is hydrogen or C₁₋₆ alkyl.

In some embodiments, R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each Vis independently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—,—N(R^(d))—C(O)—N(R^(d))—, or —C(O)N(R^(d))—; each R^(d) is independentlyhydrogen or C₁₋₆ alkyl; R⁶ is hydrogen or C₁₋₆ alkyl; and R⁹ ishydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, ornaphthyl is unsubstituted or substituted by 1-6 groups selected from—OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K. In some embodiments, K is—SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂, -CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or —P(O)(OH)₂.

In some embodiments, R⁵ is —(C₁-C₆ alkylene)-aryl, or —(C₁-C₆alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by1-6 groups selected from —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K;and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3R^(f) groups; and R⁶ is hydrogen or C₁₋₆ alkyl. In some embodiments, Kis —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or —P(O)(OH)₂.

In some embodiments, R⁵ and R⁶ are taken together with the nitrogen towhich they are attached to form a 3- to 6-membered N-heterocycloalkylwhich is unsubstituted or substituted with 1-6 groups selected from—CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; orwith 2-6 groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or —P(O)(OH)₂.

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, D is

In some embodiments, the compound has the structure of Formula (V):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof. In some embodiments of a compound of Formula (V), R² is —F,—Cl, or —CN; X is O or S; G is monocyclic 3-to 6-memberedheterocycloalkyl containing 1 oxygen atom, which is substituted with 1or 2 substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; or G is bicyclic 8- to10-membered heterocycloalkyl containing 2 oxygen atoms, which issubstituted with 1 or 2 substituents selected from —C(O)OH, —CH₂C(O)OH,—P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; D is K or —Z—NR⁵R⁶.In some embodiments, G is monocyclic 3- to 6-membered heterocycloalkylcontaining 1 oxygen atom, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is bicyclic 8- to 10-memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1or 2 substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; D is K or —Z—NR⁵R⁶

In some embodiments of a compound of Formula (V), D is K; K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl.

In some embodiments of a compound of Formula (V), D is —Z—NR⁵R⁶; Z is—(CH₂)—, —(CH(CH₃))—, —C(═O)—, or —S(═O)₂-; and R⁵ is C₆-C₁₀ alkyl thatis substituted by 5 to 9 —OH groups; or R⁵ is C₁₋₁₀ alkyl which issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6groups selected from —CO₂H, —OH, and —N(R^(d))₂; and is optionallyfurther substituted by 1, 2, or 3 R^(f) groups; or R⁵ is—[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O- , —C(R^(d))₂NR^(d)—, —N(R^(d))——C(O)—N(R^(d))—, or—C(O)N(R^(d))—; each R^(d) is independently hydrogen or C₁₋₆ alkyl; R⁹is hydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl,or naphthyl is unsubstituted or substituted by 1-6 groups selected from—OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K; or R⁵ is —(C₁-C₆alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl; wherein the aryl orheteroaryl is substituted by 1-6 groups selected from —CO₂H, —OH,—N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein the alkylene isunsubstituted or substituted by 1, 2, or 3 R^(f) groups; R⁶ is hydrogenor C₁₋₆ alkyl, which is unsubstituted or substituted by 1-3 groupsindependently selected from halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴ , —NR¹⁴C(O)NR¹⁴R¹⁴, or—P(O)(OR¹⁴)₂; or R⁵ and R⁶ are taken together with the nitrogen to whichthey are attached to form a 4- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 1-6 groups selected from —CH₃, —CH₂OH,—CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; or with 2-6groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂; and each R^(f) is independently halogen,—CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl, wherein thealkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2,or 3 halogen or —OH groups. In some embodiments, D is —Z—NR⁵R⁶; Z is—(CH₂)—, —C(═O)—, or —S(═O)₂-; and R⁵ is C₆-C₁₀ alkyl that issubstituted by 5 to 9 —OH groups; or R⁵ is C₁₋₁₀ alkyl which issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6groups selected from —CO₂H, —OH, and —N(R^(d))₂; and is optionallyfurther substituted by 1, 2, or 3 R^(f) groups; or R⁵ is—[(C(R^(d))₂)_(s—)V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, or —N(R^(d))—C(O)—N(R^(d))—; each R^(d)is independently hydrogen or C₁₋₆ alkyl; R⁹ is hydrogen, C₁₋₈ alkyl,phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl isunsubstituted or substituted by 1-6 groups selected from —OH, —CO₂H,—N(R^(e))₂, —N(R^(e))₃ ⁺, and K; or R⁵ is —(C₁-C₆ alkylene)—aryl, or—(C₁-C₆ alkylene)—heteroaryl; wherein the aryl or heteroaryl issubstituted by 1-6 groups selected from —CO₂H, —OH, —N(R^(d))₂,—N(R^(e))₃ ⁺, and K; and wherein the alkylene is unsubstituted orsubstituted by 1, 2, or 3 R^(f) groups; R⁶ is hydrogen or C₁₋₆ alkyl,which is unsubstituted or substituted by 1-3 groups independentlyselected from halogen, —CN, —OH, —OR^(—), —NR¹⁴R¹⁴, —C(O)OR¹⁴,—C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, or —P(O)(OR¹⁴)₂; and eachR^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, C(O)OR¹⁴,—C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, isunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups. Insome embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OHgroups; or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groups selectedfrom —N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH,and —N(R^(d))₂; and is optionally further substituted by 1, 2, or 3R^(f) groups; and R⁶ is hydrogen or C₁₋₆ alkyl. In some embodiments, R⁵is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups; and R⁶ ishydrogen or C₁₋₆ alkyl. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₆ alkyl.

In some embodiments of a compound of Formula (V), D is

Also disclosed herein, in some embodiment is a compound of Formula(III):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein:X is —O—or —S-;Y is N or CH;G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygenatom, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;or G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygenatoms, which is substituted with 1 or 2 substituents selected from—C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH;D is K or —Z—NR⁵R⁶;Z is —(CH₂)—, —(CH(CH₃)—, —C(═O)—, or —S(═O)₂-;K is —SO₂OH, —S(O)OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —B(OR^(d))(OH), —NHC(O)H,—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)),—NHC(O)NH(R^(d)), —N(R^(d))C(═N(R^(d))N(R^(d))₂,—N(R^(d))C(═NH)NHC(═NH)NH₂,

R^(a) and R^(b) are each independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl;each R^(d) is independently hydrogen or C₁₋₆ alkyl;each R^(e) is independently C₁₋₆ alkyl; each R² is independentlyhalogen, —CN, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, or C₃-C₆ cycloalkyl; R⁵ isC₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups;or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groups selected from—N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from —CO₂H, —OH, and—N(R^(d))₂; and is optionally further substituted by 1, 2, or 3 R^(f)groups;each R^(f) is independently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴,—C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹³, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl,is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;or R⁵ is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—, or—C(O)N(R^(d))—;or R⁵ is —(C₁-C₆ alkylene)—aryl, or —(C₁-C₆ alkylene)—heteroaryl;wherein the aryl or heteroaryl is substituted by 1-6 groups selectedfrom —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K; and wherein thealkylene is unsubstituted or substituted by 1, 2, or 3 R^(f) groups;R⁶ is hydrogen or C₁₋₆ alkyl;or R⁵ and R⁶ are taken together with the nitrogen to which they areattached to form a 3- to 6-membered N-heterocycloalkyl which isunsubstituted or substituted with 1-6 groups selected from —CH₃, —CH₂OH,—CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; or with 2-6groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂;R⁹ is hydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl,phenyl, or naphthyl is unsubstituted or substituted by 1-6 groupsselected from —OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K;each R^(—)is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-membered heterocycloalkyl,phenyl, or monocyclic heteroaryl; andeach R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to 6-memberedheterocycloalkyl, phenyl, or monocyclic heteroaryl;or two R¹⁴ on the same nitrogen atom are taken together with thenitrogen to which they are attached to form a 3- to 6-memberedN-heterocycloalkyl;p is 0 or 1;q is 0 or 1;

each s is independently 1-6; and

each t is independently 1-6.

In some embodiments, R² is halogen, —CN, C₁-C₄ alkyl, or C₁-C₄fluoroalkyl. In some embodiments, R² is —F, —Cl, —CN, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH₂F,—CHF2, or —CF₃. In some embodiments, R² is —F, —Cl, —CN, methyl, ethyl,isopropyl, or —CF₃. In some embodiments, R² is —F, —Cl, or —CN. In someembodiments, R² is —Cl.

In some embodiments, p is 1. In some embodiments, R^(a) is —F, —Cl, —CN,—OH, —O—(C₁-C₆ alkyl), C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl. In someembodiments, R^(a) is —F, —Cl, —CN, —OH, —OCH₃, —OCF₃, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH₂F,—CHF2, or —CF₃. In some embodiments, R^(a) is —F, —Cl, —CN, —OH, —OCH₃,—OCF₃, methyl, or —CF_(3.)

In some embodiments, p is 0.

In some embodiments, q is 1. In some embodiments, R^(b) is —F, —Cl, —CN,—OH, —O-(C₁-C₆ alkyl), C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl. In someembodiments, R^(b) is —F, —Cl, —CN, —OH, —OCH₃, - OCF₃, methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH₂F,—CHF2, or - CF₃. In some embodiments, R^(b) is —F, —Cl, —CN, —OH, —OCH₃,—OCF₃, methyl, or —CF₃. In some embodiments, R^(b) is —OH.

In some embodiments, q is 0.

In some embodiments, R² is —F, —Cl, or —CN; R^(a) is —F, —Cl, —CN, —OH,—OCH₃, —OCF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, —CH₂F, —CHF2, or —CF₃; and R^(b) is —F, —Cl, —CN,—OH, —OCH₃, —OCF₃, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, tert-butyl, —CH₂F, —CHF₂, or —CF₃. In some embodiments, R² is—Cl; p is 0; q is 0 or 1; and R^(b) is —OH.

In some embodiments, the compound has the structure of Formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.

In some embodiments, X is —O—. In some embodiments, X is —S—.

In some embodiments, G is monocyclic 3- to 6-membered heterocycloalkylcontaining 1 oxygen atom, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is monocyclic 3- to 6-memberedheterocycloalkyl containing 1 oxygen atom, which is substituted with 1or 2 substituents selected from —C(O)OH, —OH, and —CH₂OH.

In some embodiments, G is bicyclic 8- to 10-membered heterocycloalkylcontaining 2 oxygen atoms, which is substituted with 1 or 2 substituentsselected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH,—OH, and —CH₂OH. In some embodiments, G is bicyclic 8- to 10-memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1or 2 substituents selected from —C(O)OH, —OH, and —CH₂OH. In someembodiments, G is bicyclic 8- to 10-membered heterocycloalkyl containing2 oxygen atoms, which is substituted with 1 or 2 substituents selectedfrom —OH and —CH₂OH. In some embodiments, G is bicyclic 8- to 10memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1substituent selected from —OH and —CH₂OH. In some embodiments, G isbicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygen atoms,which is substituted with 1 —OH substituent.

In some embodiments, —X-G is selected from:

and

In some embodiments, —X-G is:

In some embodiments, —X-G is:

In some embodiments, —X-G is:

In some embodiments, —X-G is:

In some embodiments, Y is N. In some embodiments, Y is CH.

In some embodiments, D is K. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)), —SO₂NHC(O)(R^(d)),—NHC(O)NH(R^(d)),

In some embodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)),—SO₂NHC(O)(R^(d)), —NHC(O)NH(R^(d)),

or

In some embodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)). In someembodiments, each R^(d) is independently hydrogen or C₁₋₆ alkyl. In someembodiments, K is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and eachR^(d) is independently hydrogen or C₁₋₆ alkyl. In some embodiments, K is—SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or C₁₋₃ alkyl. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and each R^(d) is independentlyhydrogen or methyl. In some embodiments, K is —SO₂OH, —P(O)(OH)₂,—CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In someembodiments, K is —SO₂OH or —P(O)(OH)₂. In some embodiments, K is—SO₂OH. In some embodiments, K is —P(O)(OH)₂.

In some embodiments, D is —SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)),—CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)); and eachR^(d) is independently hydrogen or C₁₋₆ alkyl. In some embodiments, D is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe). In some embodiments, D is —SO₂OH or —P(O)(OH)₂. In someembodiments, D is —SO₂OH. In some embodiments, D is —P(O)(OH)₂.

In some embodiments, D is -Z-NR⁵R⁶.

In some embodiments, Z is —(CH₂)—, —C(═O)—, or —S(═O)₂—. In someembodiments, Z is —(CH₂)—. In some embodiments, Z is —(CH(CH₃)—. In someembodiments, Z is —C(═O)—or —S(═O)₂—. In some embodiments, Z is —C(═O)—.In some embodiments, Z is —S(═O)₂—.

In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9—OH groups. In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substitutedby 5 —OH groups.

In some embodiments, R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6 groups selectedfrom —CO₂H, —OH, and —N(R^(d))₂; and is optionally further substitutedby 1, 2, or 3 R^(f) groups; and each R^(f) is independently halogen,—CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or phenyl, wherein thealkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2,or 3 halogen or —OH groups.

In some embodiments, R⁵ is —[(C(R^(d))₂)_(s)-V]_(t)—R⁹; wherein each Vis independently —C(R^(d))₂O—, —C(R^(d))₂NR^(d)—,—N(R^(d))—C(O)—N(R^(d))—, or —C(O)N(R^(d))—; each R^(d) is independentlyhydrogen or C₁₋₆ alkyl; R⁶ is hydrogen or C₁₋₆ alkyl; and R⁹ ishydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, ornaphthyl is unsubstituted or substituted by 1-6 groups selected from—OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K. In some embodiments, K is—SO₂OH, —P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)). In some embodiments, K is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe). In some embodiments, K is —SO₂OH or —P(O)(OH)₂. In someembodiments, K is —SO₂OH. In some embodiments, K is —P(O)(OH)₂.

In some embodiments, R⁵ and R⁶ are taken together with the nitrogen towhich they are attached to form a 3- to 6-membered N-heterocycloalkylwhich is unsubstituted or substituted with 1-6 groups selected from—CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, —N(R^(e))₃ ⁺, and K; orwith 2-6 groups selected from —CO₂H, —OH, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH,—CH₂OCH₂CH₂OH, and —N(R^(d))₂. In some embodiments, R⁵ and R⁶ are takentogether with the nitrogen to which they are attached to form a 4- to6-membered N-heterocycloalkyl which is substituted with 2-4 groupsselected from —OH and —CH₂OH. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)). In some embodiments, K is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe). In some embodiments, K is —SO₂OH or —P(O)(OH)₂. In someembodiments, K is —SO₂OH. In some embodiments, K is —P(O)(OH)₂.

In some embodiments, R⁵ is C₆-C₁₀ alkyl that is substituted by 5 to 9—OH groups; or R⁵ is C₁₋₁₀ alkyl which is substituted by 1-6 groupsselected from —N(R^(e))₃ ⁺ and K; or with 2-6 groups selected from—CO₂H, —OH, and —N(R^(d))₂; and is optionally further substituted by 1,2, or 3 R^(f) groups. In some embodiments, K is —SO₂OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—C(O)NHSO₂(R^(d)), or —SO₂NHC(O)(R^(d)). In some embodiments, K is—SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe). In some embodiments, K is —SO₂OH or —P(O)(OH)₂. In someembodiments, K is —SO₂OH. In some embodiments, K is —P(O)(OH)₂.

In some embodiments, D is

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

In some embodiments, the compound is a compound in one of the followingtables, or a pharmaceutically acceptable salt, solvate, stereoisomer, orprodrug thereof.

TABLE 1 Cmpd No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

14

22

29

30

31

32

33

36

37

38

40

45

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

Compounds in Table 1 are named:

1:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide;

2:(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid;

3:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide;

4:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol;

5:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid;

6:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonicacid;

7:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)-2-(4-chlorophenyl)propane-1-sulfonicacid;

8:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid;

9:2-(N-(2-amino-2-oxoethyl)-4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid;

10: 5-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)amino)naphthalene-1-sulfonicacid;

11:4-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)benzenesulfonicacid;

12:(4′-(6-chloro-2-(((3R,5S,6R)—5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid;

14:(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)phosphonicacid;

22:3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-hydroxypropanoicacid;

29:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)-N,N,N-trimethylethan-1-aminium;

30:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1′-biphenyl]-4-carboxamide;

31:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide;

32:1-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium;

33:1-(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium;

36:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol;

37:4-((((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-hydroxyethyl)butanamide;38:4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(1,3-dihydroxypropan-2-yl)butanamide;40:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)propane-1,3-diol;45:(4′-(6-chloro-2-(((3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid;48:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-carboxamide;49:(3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;50:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;51:(3R,3aR,6R,6aR)-6-((6-chloro-5-((4′-(4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;52:(1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol;53:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol;54:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol;55:(3R,3aR,6R,6aR)-6-((6-chloro-5-((4′-((4-(hydroxymethyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-o;56:(3R,3aR,6R,6aR)-6-(((6-chloro-5-(4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;57: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;58:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;59:(R)-1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)[1,1′-biphenyl]-4-yl)methyl)pyrrolidin-3-ol;60:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol;61:(3S,4R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol;62:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)(methyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;63:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((3-(hydroxymethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;64:(3S,4S)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol;65:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol;66:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol;67:(3R,3aR,6R,6aR)-6-((5-(4′-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;68:(4′-(6-chloro-2-(((3R,4S,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid;69:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-sulfonicacid;70:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-sulfonamide;71:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide;72:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-sulfonamide;73:(2R,3R,4R,5S)-6-(1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)ethyl)amino)hexane-1,2,3,4,5-pentaol;74:(3R,3aR,6R,6aR)-6-((6-chloro-5-(2′-hydroxy-4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;75:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide.

In some embodiments, the compound is a pharmaceutically acceptable saltof a compound in Table 1.

TABLE 2 Cmpd No. Structure 13

15

16

17

18

19

20

21

23

24

25

26

27

28

34

35

39

41

42

43

44

46

Compounds in Table 2 are named:

13:(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)phosphonicacid;

15:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonicacid;

16:(4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonicacid);

17:(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2,3-dihydro-1H-inden-2-yl)phosphonic acid;

18:(S)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-3-(4-(phosphonomethyl)phenyl)propanoicacid;

19:N-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(phosphonomethyl)glycine;

20: 3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)pentanedioicacid;

21:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-4-(hydroxy(methyl)phosphoryl)butanoicacid;

23:((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-L-asparticacid;

24:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)hexane-1,2,3,4,5-pentaol;

25:(2R,3R,4R,5S)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol;

26:(4-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)butyl)phosphonicacid;

27:(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonicacid;

28:((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(phosphonomethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonicacid;

34:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(1,3-dihydroxypropan-2-yl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide;

35:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(2-hydroxyethyl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide;

39:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)-N,N,N-trimethylethan-1-aminium;

41:1-(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)-3-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)urea;

42:(1R,2S,3R,5R)-3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol;

43:(2R,3R)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)butane-1,3-diol;

44:2-(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)guanidine;46:2-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide.

In some embodiments, the compound is a pharmaceutically acceptable saltof a compound in Table 2.

Further Forms of Compounds

Furthermore, in some embodiments, the compounds described herein existas “geometric isomers.” In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (F), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. In someembodiments, the compounds presented herein exist as tautomers. Incircumstances where tautomerization is possible, a chemical equilibriumof the tautomers will exist. The exact ratio of the tautomers depends onseveral factors, including physical state, temperature, solvent, and pH.Some examples of tautomeric equilibrium include:

In some situations, the compounds described herein possess one or morechiral centers and each center exists in the (R)- configuration or (S)-configuration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization.

The term “positional isomer” refers to structural isomers around acentral ring, such as ortho-, meta-, and para- isomers around a benzenering.

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds described herein, as well as activemetabolites of these compounds having the same type of activity.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S.M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

“Prodrug” is meant to indicate a compound that is, in some embodiments,converted under physiological conditions or by solvolysis to an activecompound described herein. Thus, the term prodrug refers to a precursorof an active compound that is pharmaceutically acceptable. A prodrug istypically inactive when administered to a subject, but is converted invivo to an active compound, for example, by hydrolysis. The prodrugcompound often offers advantages of solubility, tissue compatibility ordelayed release in a mammalian organism (see, e.g., Bundgard, H., Designof Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugsas Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of an active compound, asdescribed herein, are prepared by modifying functional groups present inthe active compound in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent activecompound. Prodrugs include compounds wherein a hydroxy, amino, carboxy,or mercapto group is bonded to any group that, when the prodrug of theactive compound is administered to a mammalian subject, cleaves to forma free hydroxy, free amino, free carboxy, or free mercapto group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol or amine functionalgroups in the active compounds and the like.

“Pharmaceutically acceptable solvate” refers to a composition of matterthat is the solvent addition form. In some embodiments, solvates containeither stoichiometric or non-stoichiometric amounts of a solvent, andare formed during the process of making with pharmaceutically acceptablesolvents such as water, ethanol, and the like. “Hydrates” are formedwhen the solvent is water, or “alcoholates” are formed when the solventis alcohol. Solvates of compounds described herein are convenientlyprepared or formed during the processes described herein. The compoundsprovided herein optionally exist in either unsolvated as well assolvated forms.

The compounds disclosed herein, in some embodiments, are used indifferent enriched isotopic forms, e.g., enriched in the content of ²H,³H, ¹¹C, ¹³C and/or ¹⁴C. In some embodiments, the compound is deuteratedin at least one position. Such deuterated forms can be made by theprocedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. Asdescribed in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration canimprove the metabolic stability and or efficacy, thus increasing theduration of action of drugs.

Unless otherwise stated, structures depicted herein are intended toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C—or ¹⁴C-enriched carbonare within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnaturalproportions of atomic isotopes at one or more atoms that constitute suchcompounds. For example, the compounds may be labeled with isotopes, suchas for example, deuterium (²H), tritium (³H), iodine-125 (¹²⁵I) orcarbon-14 (¹⁴C) Isotopic substitution with ²H, ³H, ¹¹C, ¹³C, 14C, ¹⁵C,¹²N, ¹³N, ¹⁵N, ¹⁶N, ¹⁷O, ¹⁸O, ¹⁴F, ¹⁵F, ¹⁶F, ¹⁷F, ¹⁸F, ³³S, ³⁴S, ³⁵S,³⁶S, ³⁵CL, ³⁷CL, ⁷⁹Br, ⁸¹Br, ¹²⁵I are all contemplated. All isotopicvariations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

In some embodiments, the compounds disclosed herein have some or all ofthe ¹H atoms replaced with ²H atoms. The methods of synthesis fordeuterium-containing compounds are known in the art. In some embodimentsdeuterium substituted compounds are synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)]2000, 110 pp;George W.; Varma, Rajender S. The Synthesis of Radiolabeled

Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21),6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J.Radioanal. Chem., 1981, 64(1-2), 9-32.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In some embodiments, the compounds described herein, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, as described herein are substantially pure, in that it containsless than about 5%, or less than about 1%, or less than about 0.1%, ofother organic small molecules, such as contaminating intermediates orby-products that are created, for example, in one or more of the stepsof a synthesis method. Preparation of the Compounds

Compounds described herein are synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6th Edition, John Wiley and Sons, Inc. Alternative reaction conditionsfor the synthetic transformations described herein may be employed suchas variation of solvent, reaction temperature, reaction time, as well asdifferent chemical reagents and other reaction conditions.

In some embodiments, compounds described herein are prepared as outlinedin the Scheme below.

Briefly, nitropyridine compound A is reduced to bis-amino-pyridinecompound B. Compound B is treated with thiophosgene to afford compoundC. Compound C undergoes a methylation reaction following by oxidation toafford compound D. Compound D is protected with a suitable protectinggroup, then undergoes a substitution reaction with a suitable alcohol toafford compound E. Aryl iodide E is treated under cross-couplingconditions, for example Suzuki cross- coupling, to arrive at compound F.Finally, protecting group removal yields final compound G. In someinstances, additional chemical modification, such as amide formation orreductive amination, is performed on compound F before finaldeprotection to compound G. In other embodiments, such modifications areperformed directly on compound G to provide further compounds.

In some embodiments, compounds described herein are prepared asdescribed as outlined in the Examples.

Pharmaceutical Compositions

In some embodiments, disclosed herein is a pharmaceutical compositioncomprising an AMPK activator described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, and at leastone pharmaceutically acceptable excipient. In some embodiments, the AMPKactivator is combined with a pharmaceutically suitable (or acceptable)carrier (also referred to herein as a pharmaceutically suitable (oracceptable) excipient, physiologically suitable (or acceptable)excipient, or physiologically suitable (or acceptable) carrier) selectedon the basis of a chosen route of administration, e.g., oraladministration, and standard pharmaceutical practice.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof; vegetable oils, such as olive oil; andinjectable organic esters, such as ethyl oleate and cyclodextrins.Proper fluidity is maintained, for example, by the use of coatingmaterials, such as lecithin; by the maintenance of the required particlesize, in the case of dispersions; and by the use of surfactants.Combination Therapies

In some embodiments, it is appropriate to administer at least onecompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, in combination with one ormore other therapeutic agents.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, isadministered in combination with one or more anti- inflammatory agents.Examples of anti-inflammatory agents to be used in combination with acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include, but are not limitedto: aminosalicylates such as balsalazide, mesalamine, olsalazine, andsulfalazine; corticosteroids such as budesonide, prednisone,prednisolone, methylprednisolone, dexamethasone, and betamethasone;anti-TNF alpha agents such as infliximab, adalimumab, certolizumabpegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents such asustekinumab, guselkumab, brazikumab, mirikizumab, risankizumab, andPTG-200; anti-integrin agents such as natalizumab, vedolizumab,etrolizumab, SHP 647 (PF-00547659), alicaforsen, abrilumab, AJM300, andPTG-100; JAK inhibitors such as tofacitinib, filgotinib, peficitinib,itacitinib, ABT-494, and TD- 1473; S1P1R modulators such as ozanimod,amiselimod, etrasimod, and CBP-307; salicylates such as aspirin,salicylic acid, gentisic acid, choline magnesium salicylate, cholinesalicylate, choline magnesium salicylate, choline salicylate, magnesiumsalicylate, sodium salicylate, and diflunisal; COX inhibitors such ascarprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen,ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen,oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin,meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, andmeloxicam; COX-2 specific inhibitors such as, but not limited to,celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib,CS-502, JTE-522, L-745 337, and NS398; and IL-22 agents such as RG-7880.In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, isadministered in combination with a aminosalicylate, a corticosteroid, ananti-TNF alpha agent, an anti-IL-12 and/or NB-23 agent, an anti-integrinagent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COXinhibitor, a COX-2 specific inhibitor, an interleukin-22 (IL-22) agent,or a combination thereof.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, isadministered in combination with one or more agents that improvegastrointestinal barrier function. Examples of agents that improvegastrointestinal barrier function to be used in combination with acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include, but are not limitedto: HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004; MC1Ragonists such as PL-8177; EZH2 inhibitors such as IMU-856; and DPP-4inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin,gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin,evogliptin, gosogliptin, and dutogliptin. In some embodiments, acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, is administered incombination with a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH)inhibitor, a melanocortin- 1 receptor (MC1R) agonist, an enhancer ofzeste homolog 2 (EZH2) inhibitor, or combinations thereof.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, isadministered in combination with a glucagon-like peptide (GLP)-1agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisomeproliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor(FXR) agonist, a TGR5 agonist, a GPR40 agonist, a GPR119 agonist, anSSTR5 antagonist, an SSTR5 inverse agonist, an acetyl-CoA carboxylase(ACC) inhibitor, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, adipeptidyl peptidase 4 (DPP-4) inhibitor, or combinations thereof. Insome embodiments, the pharmaceutical composition comprises one or moreanti-diabetic agents. In some embodiments, the pharmaceuticalcomposition comprises one or more anti-obesity agents. In someembodiments, the pharmaceutical composition comprises one or more agentsto treat nutritional disorders.

Examples of a GLP-1 agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: exenatide, liraglutide,taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide,OWL833 and ORMD 0901.

Examples of a GLP-2 agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: tedaglutide, glepaglutide(ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912,NB-1002, GX-G8, PE-0503, and SAN-134, and those described inWO-2011050174, WO-2012028602, WO-2013164484, WO-2019040399,WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559,WO-2017002786, WO-2010042145, WO-2008056155, WO-2007067828,WO-2018229252, WO-2013040093, WO-2002066511, WO-2005067368,WO-2009739031, WO-2009632414, and WO-2008028117

Examples of a GLP-1/2 co-agonist to be used in combination with acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include ZP- GG-72 and thosedescribed in WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560,WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440..

Examples of a PPAR agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: elafibranor (GFT505),lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar, andGW501516.

Examples of a FXR agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: obeticholic acid, NGM-282,EYP001, GS-9674, tropifexor (LJN452), and LMB-763.

Examples of a TGR5 agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: INT-777, XL-475, SRX-1374,RDX-8940, RDX-98940, SB-756050, and those disclosed in WO-2008091540,WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739,WO-2018005794, WO-2016054208, WO-2015160772, WO-2013096771,WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846,WO-2012082947, WO-2012149236, WO-2008097976, WO-2016205475,WO-2015183794, WO-2013054338, WO-2010059859, WO-2010014836,WO-2016086115, WO-2017147159, WO-2017147174, WO-2017106818,WO-2016161003, WO-2014100025, WO-2014100021, WO-2016073767,WO-2016130809, WO-2018226724, WO-2018237350, WO-2010093845,WO-2017147137, WO-2015181275, WO-2017027396, WO-2018222701,WO-2018064441, WO-2017053826, WO-2014066819, WO-2017079062,WO-2014200349, WO-2017180577, WO-2014085474.

Examples of a GPR40 agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: fasiglifam, MR-1704, SCO-267,SHR-0534, HXP-0057-SS, LY-2922470, P-11187, JTT-851, ASP- 4178, AMG-837,ID-11014A, HD-C₇₁₅, CNX-011-67, JNJ-076, TU-5113, HD-6277, MK-8666,LY-2881835, CPL-207-280, ZYDG-2, and those described in US-07750048,WO-2005051890, WO-2005095338, WO-2006011615, WO-2006083612,WO-2006083781, WO-2007088857, WO-2007123225, WO-2007136572,WO-2008054674, WO-2008054675, WO-2008063768, WO-2009039942,WO-2009039943, WO-2009054390, WO-2009054423, WO-2009054468,WO-2009054479, WO-2009058237, WO-2010085522, WO-2010085525,WO-2010085528, WO-2010091176, WO-2010123016, WO-2010123017,WO-2010143733, WO-2011046851, WO-2011052756, WO-2011066183,WO-2011078371, WO-2011161030, WO-2012004269, WO-2012004270,WO-2012010413, WO-2012011125, WO-2012046869, WO-2012072691,WO-2012111849, WO-2012147518, WO-2013025424, WO-2013057743,WO-2013104257, WO-2013122028, WO-2013122029, WO-2013128378,WO-2013144097, WO-2013154163, WO-2013164292, WO-2013178575,WO-2014019186, WO-2014073904, WO-2014082918, WO-2014086712,WO-2014122067, WO-2014130608, WO-2014146604,WO-2014169817,WO-2014170842,WO-2014187343, WO-2015000412, WO-2015010655, WO-2015020184,WO-2015024448, WO-2015024526, WO-2015028960, WO-2015032328,WO-2015044073, WO-2015051496, WO-2015062486, WO-2015073342,WO-2015078802, WO-2015084692, WO-2015088868, WO-2015089809,WO-2015097713, WO-2015105779, WO-2015105786, WO-2015119899,WO-2015176267, WO-201600771, WO-2016019587, WO-2016022446,WO-2016022448, WO-2016022742, WO-2016032120, WO-2016057731,WO-2017025368, WO-2017027309, WO-2017027310, WO-2017027312,WO-2017042121, WO-2017172505, WO-2017180571, WO-2018077699,WO-2018081047, WO-2018095877, WO-2018106518, WO-2018111012,WO-2018118670, WO-2018138026, WO-2018138027, WO-2018138028,WO-2018138029, WO-2018138030, WO-2018146008, WO-2018172727,WO-2018181847, WO-2018182050, WO-2018219204, WO-2019099315, andWO-2019134984.

Examples of a GPR119 agonist to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: DS-8500a, HD-2355, LC34AD3,PSN-491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241, andthose described in WO-2009141238, WO-2010008739, WO-2011008663,WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414,WO-2011025006, WO-2012046249, WO-2009106565, WO-2011147951,WO-2011127106, WO-2012025811, WO-2011138427, WO-2011140161,WO-2011061679, WO-2017175066, WO-2017175068, WO-2015080446,WO-2013173198, US-20120053180, WO-2011044001, WO-2010009183,WO-2012037393, WO-2009105715, WO-2013074388, WO-2013066869,WO-2009117421, WO-201008851, WO-2012077655, WO-2009106561,WO-2008109702, WO-2011140160, WO-2009126535, WO-2009105717,WO-2013122821, WO-2010006191, WO-2009012275, WO-2010048149,WO-2009105722, WO-2012103806, WO-2008025798, WO-2008097428,WO-2011146335, WO-2012080476, WO-2017106112, WO-2012145361,WO-2012098217, WO-2008137435, WO-2008137436, WO-2009143049,WO-2014074668, WO-2014052619, WO-2013055910, WO-2012170702,WO-2012145604, WO-2012145603, WO-2011030139, WO-2018153849,WO-2017222713, WO-2015150565, WO-2015150563, WO-2015150564,WO-2014056938, WO-2007120689, WO-2016068453, WO-2007120702,WO-2013167514, WO-2011113947, WO-2007003962, WO-2011153435,WO-2018026890, WO-2011163090, WO-2011041154, WO-2008083238,WO-2008070692, WO-2011150067, and WO-2009123992.

Examples of a SSTR5 antagonist or inverse agonist to be used incombination with a compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, includethose described in: WO-03104816, WO-2009050309, WO-2015052910,WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183, andWO-2016205032.

Examples of an ACC inhibitor to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: firsocostat, GS-834356, andPF-05221304.

Examples of a SCD-1 inhibitor to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include aramchol.

Examples of a DPP-4 inhibitor to be used in combination with a compounddescribed herein, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, include: sitagliptin, vildagliptin,saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin,trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.

Examples of anti-diabetic agents to be used in combination with acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptoragonists such as exenatide, liraglutide, taspoglutide, lixisenatide,albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2inhibitors such as dapagliflozin, canagliflozin, empagliflozin,ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin,sergliflozin, sotagliflozin, and tofogliflozin; biguinides such asmetformin; insulin and insulin analogs.

Examples of anti-obesity agents to be used in combination with acompound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptoragonists such as liraglutide, semaglutide; SGLT1/2 inhibitors such asLIK066, pramlintide and other amylin analogs such as AM-833, AC2307, andBI 473494; PYY analogs such as NN-9747, NN-9748, AC-162352, AC-163954,GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such asAPD-668 and APD-597; GLP-1/GIP co-agonists such as tirzepatide(LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090-2746, RG-7685,NN-9709, and SAR-438335; GLP-1/glucagon co-agonist such as cotadutide(MEDI0382), BI 456906, TT-401, G-49, H&D-001A, ZP-2929, and HM-12525A;GLP-1/GIP/glucagon triple agonist such as SAR-441255, HM-15211, andNN-9423; GLP-1/secretin co-agonists such as GUB06-046; leptin analogssuch as metreleptin; GDF15 modulators such as those described inWO-2012138919, WO-2015017710, WO-2015198199, WO-2017147742 andWO-2018071493; FGF21 receptor modulators such as NN9499, NGM386, NGM313,BFKB8488A (RG7992), AKR-001, LLF-580, CVX-343, LY-2405319, BIO89-100,and BMS-986036; MC4 agonists such as setmelanotide; MetAP2 inhibitorssuch as ZGN-1061; ghrelin receptor modulators such as HM04 and AZP-531;and oxytocin analogs such as carbetocin.

Examples of agents for nutritional disorders to be used in combinationwith a compound described herein, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof, include: GLP-2 receptoragonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide(ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503,SAN-134, and those described in WO-2011050174, WO-2012028602,WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209,WO-2006117565, WO-2019086559, WO-2017002786, WO-2010042145,WO-2008056155, WO-2007067828, WO-2018229252, WO-2013040093,WO-2002066511, WO-2005067368, WO-2009739031, WO-2009632414, andWO-2008028117; and GLP-1/GLP-2 receptor co-agonists such as ZP-GG-72 andthose described in WO-2018104561, WO-2018104558, WO-2018103868,WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, andWO-2014096440.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound described herein, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, is co-administered with one or more additional therapeuticagents, wherein the compound described herein, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, and theadditional therapeutic agent(s) modulate different aspects of thedisease, disorder or condition being treated, thereby providing agreater overall benefit than administration of either therapeutic agentalone. In some embodiments, the additional therapeutic agent(s) is aglucagon-like peptide (GLP)-1 agonist, a GLP-2 agonist, a GLP-1/2co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist,a Farsnenoid X receptor (FXR) agonist, a stearoyl-CoA desaturase 1(SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or acombination thereof. In some embodiments, the second therapeutic agentis an anti-inflammatory agent. In some embodiments, the additionaltherapeutic agent(s) is an aminosalicylate, a corticosteroid, ananti-TNF alpha agent, an anti-IL-12 and/or 23 agent, an anti-integrinagent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COXinhibitor, a COX-2 specific inhibitor, an IL-22 agent, or a combinationthereof. In some embodiments, the second therapeutic agent is an agentthat improves gastrointestinal barrier function. In some embodiments,the additional therapeutic agent(s) is a HIF-PH inhibitor, an MC1Ragonist, an EZH2 inhibitor, or a combination thereof.

In some embodiments, the overall benefit experienced by the patient isadditive of the two (or more) therapeutic agents. In other embodiments,the patient experiences a synergistic benefit of the two (or more)therapeutic agents.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds described herein, or pharmaceutically acceptable salts,solvates, stereoisomers, or prodrugs thereof, as well as combinationtherapies, are administered before, during or after the occurrence of adisease or condition, and the timing of administering the compositioncontaining a compound varies. Thus, in one embodiment, the compoundsdescribed herein are used as a prophylactic and are administeredcontinuously to subjects with a propensity to develop conditions ordiseases in order to prevent the occurrence of the disease or condition.In another embodiment, the compounds and compositions are administeredto a subject during or as soon as possible after the onset of thesymptoms. In specific embodiments, a compound described herein isadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease.

In some embodiments, a compound described herein, or a pharmaceuticallyacceptable salt thereof, is administered in combination withanti-inflammatory agent, anti-cancer agent, immunosuppressive agent,steroid, non-steroidal anti-inflammatory agent, antihistamine,analgesic, hormone blocking therapy, radiation therapy, monoclonalantibodies, or combinations thereof.

EXAMPLES

List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

ACN or MeCN acetonitrile AcOH or HOAc acetic acid AcCl acetyl chlorideADP adenosine diphosphate AMP adenosine monophosphate AMPK 5′AMP-activated protein kinase or adenosine 5′-monophosphate-activatedprotein kinase ATP adenosine triphosphate aq aqueous BPDbis(pinacolato)diboron DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCMdichloromethane DIEA or DIPEA N,N-diisopropylethylamine DMAP4-dimethylaminopyridine DME dimethoxyethane DMF dimethylformamide DMSOdimethyl sulfoxide DMTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride eq equivalent(s) Et ethyl EtOH ethanol EtOAc or EAethyl acetate FA formic acid h, hr(s) hour(s) HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate HPLC high performance liquid chromatographyKOAc potassium acetate LCMS liquid chromatography-mass spectrometry Memethyl MeOH methanol MeI methyl iodide min(s) minute(s) MS massspectroscopy or molecular sieves NCS N-chlorosuccinimide NMR nuclearmagnetic resonance Oxone potassium peroxysulfate Pd(dppf)Cl₂[1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(II)Pd(dppf)Cl′2•CH₂Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex RP-MPLC reverse phasemedium pressure liquid chromatography SEM 2-(trimethylsilyl)ethoxymethylSEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride rt or RT room temperatureTBS tert-butyldimethylsilyl TBS-Cl tert-butyldimethylsilyl chlorideTMSBr trimethylsilyl bromide tBu tert-butyl tBu₃P•Pd•G2chloro[(tri-tert-butylphosphine)-2-(2- aminobiphenyl)] palladium(II) TEAtriethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thinlayer chromatography

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted.

Example 1:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide(Compound 1)

Step 1:(3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-ol(1-1):To a solution of(3R,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol (24 g,0.16 mol, 1 eq) and imidazole (25 g, 0.37 mmol, 2.25 eq) in DMF (240 mL)was added TBSC1 (27 g, 0.18 mol, 22 mL, 1.1 eq). The mixture was stirredat room temperature for 1.25 hrs. The mixture was poured into water (200mL) and then extracted with ethyl acetate (3×300 mL). The combinedorganic layers were washed with saturated brine (2×100 mL), thenconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, petroleum ether : ethyl acetate=5:1 to 1:1) to give 1-1 (18 g,43% yield) as a white solid. ¹H-NMR (CD₃OD, 400 MHz): δ 4.52 (t, J=5.6Hz, 1H), 4.43 (t, J=5.2 Hz, 1H), 4.27 (q, J=5.2 Hz, 1H), 4.23-4.17 (m,1H), 3.99-3.93 (m, 2H), 3.78-3.73 (m, 2H), 3.19 (d, J=9.2 Hz, 1H), 0.92(s, 9H), 0.13 (s, 3H), 0.12 (s, 3H).

Step 2: 5,6-dichloro-3-nitropyridin-2-amine (1-2): To a solution of6-chloro-3-nitro-pyridin-2-amine (50 g, 0.29 mol, 1 eq) in AcOH (250 mL)was added NCS (46 g, 0.35 mmol, 1.2 eq). The mixture was stirred at 100°C. for 3 hrs. The mixture was cooled to room temperature, then filtered.The filter cake was washed with ethanol (100 mL), then dried in vacuo togive 1-2 (48 g, crude) as a yellow solid. LCMS (ES⁺): m/z (M+H)⁺=207.9.

Step 3: 5-chloro-6-iodo-3-nitropyridin-2-amine (1-3): To a solution of1-2 (48 g, 0.23 mol, 1 eq) in AcOH (250 mL) was added NaI (73 g, 0.48mol, 2.1 eq). The mixture was stirred at 90 ° C. for 12 hrs. The mixturewas poured into water (500 mL), then filtered. The filter cake waswashed with water (200 mL), then dried in vacuo to give 1-3 (60 g,crude) as a yellow solid. LCMS (ES⁺): m/z (M+H)⁺=299.8.

Step 4: 5-chloro-6-iodopyridine-2,3-diamine (1-4): To a solution 1-3 of(60 g, 0.20 mol, 1 eq) in EtOH (300 mL) was added SnCl₂·2HO (0.18 kg,0.80 mol, 4 eq). The mixture was stirred at 70° C. for 0.5 hr. To themixture was added water (450 mL) and KF (0.18 kg), and the mixture wasstirred for 0.5 h, then extracted with ethyl acetate (2×100 mL). Theorganic phase was washed with saturated brine (2×50 mL), thenconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, petroleum ether : ethyl acetate=2:1 to 0:1) to give 1-4 (41 g,73% yield, 96% purity) as an off-white solid. LCMS (ES⁺): m/z(M+H)⁺=269.9.

Step 5: 6-chloro-5-iodo-1H-imidazo[4,5-b]pyridine-2(3H)-thione (1-5): Toa solution of 1-4 (20 g, 74 mmol, 1 eq) and DMAP (26 g, 0.22 mol, 2.9eq) in THF (400 mL) was added dropwise thiocarbonyl dichloride (12 g,0.10 mol, 8.0 mL, 1.4 eq) at 0° C. under N₂. The mixture was stirred atroom temperature for 24 hr. To the reaction mixture was added ethylacetate (2000 mL) and 2 N aqueous HCl (200 mL). The organic layer waswashed with saturated brine (2×300 mL), then concentrated in vacuo togive 1-5 (17 g) as a yellow solid. LCMS (ES⁺): m/z (M+H)⁺=311.8.

Step 6: 6-chloro-5-iodo-2-(methylthio)-3H-imidazo[4,5-b]pyridine (1-6):A solution of 1-5 (22 g, 70 mmol, 1 eq) and KOH (4.7 g, 84 mmol, 1.2 eq)in EtOH (440 mL) was stirred at room temperature for 0.5 hr. MeI (10.0g, 70 mmol, 4.4 mL, 1 eq) was added, and the reaction was stirred atroom temperature for another 1 hr. The reaction mixture was concentratedin vacuo to give a residue, then ethyl acetate (300 mL) was addedfollowed by 2 N aqueous HCl (50 mL). The organic layer was washed withsaturated brine (2×50 mL), then concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether : ethylacetate=5:1 to 1:1) to give 1-6(16 g, 48% yield, 68% purity) as a yellowsolid. added m/z (M+H)⁺=325.8.

Step 7: 6-chloro-5-iodo-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine(1-7): To a solution of 1-6 (16 g, 49 mmol, 1 eq) in ACN (320 mL) andH₂O (320 mL) was added Oxone (66 g, 0.11 mmol, 2.2 eq). The mixture wasstirred at room temperature for 12 hrs. The mixture was extracted withethyl acetate (3×400 mL). The combined organic layers were washed withsaturated Na₂SO₃ solution (2×200 mL) and brine (2×200 mL), thenconcentrated in vacuo to give 1-7 (16 g) as a yellow solid which wasused for next step directly. LCMS (ES⁺): m/z (M+H)⁺=357.8.

Step 8:6-chloro-5-iodo-2-(methylsulfonyl)-1-((trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(1-8): SEM-Cl (7.3 g, 44 mmol, 7.7 mL, 1 eq) was added dropwise to a THF(310 mL) solution of 1-7 (16 g, 44 mmol, 1 eq) and TEA (6.6 g, 65 mmol,9.1 mL, 1.5 eq) at 0° C. under nitrogen. The reaction mixture wasstirred at room temperature for 0.5 hr. The mixture was poured intowater (100 mL) and then extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with saturated brine (2×100 mL),then concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, petroleum ether : ethyl acetate=10:1 to 5:1) togive 1-8 (12 g, 56% yield, 98% purity) as a yellow solid. LCMS (ES⁺):m/z (M+Na)⁺=510.0.

Step 9:2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-5-iodo-1-((trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(1-9): To a solution of 1-8 (12 g, 25 mmol, 1 eq) and 1-1 (8.0 g, 31mmol, 1.2 eq) in DMF (125 mL) was added C_(s2)CO₃ (17 g, 51 mmol, 2 eq)under N₂. The mixture was stirred at room temperature for 4 hrs. Themixture was poured into water (100 mL) and then extracted with ethylacetate (2×200 mL). The combined organic layers were washed withsaturated brine (2×50 mL), then concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, petroleum ether : ethylacetate=20:1 to 5:1) to give 1-9 (10 g, 53% yield, 90% purity) as ayellow solid. LCMS (ES⁺): m/z (M+H)⁺=668.2. ¹H-NMR (DMSO-d₆, 400 MHz): δ8.07 (s, 1H), 5.50 -5.46 (m, 1H), 5.37 (s, 2H), 4.82 (t, J=5.2 Hz, 1H),4.37-4.35 (m, 2H), 4.32- 4.23 (m, 2H), 4.00-3.94 (m, 1H), 3.79 -3.71 (m,2H), 3.61 (t, J=8.4 Hz, 1H), 0.87 (s, 9H), 0.08- 0.05 (m, 8H), −0.07 (s,9H).

Step

10: methyl 4′-(2-(((3R,3aR,6R,6aS)-6-((tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxylate(1-10): To a solution of 1-9 (0.50 g, 0.75 mmol) and(4′-(methoxycarbonyl)-[1,1′-biphenyl]-4-yl)boronic acid (0.23 g, 0.90mmol) in DME (10 mL) and H₂O (2 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (0.12 g,0.15 mmol) and Na₂CO₃ (0.24 g, 2.2 mmol) under N₂. The mixture wasstirred at 90° C. for 2 hr. The reaction mixture was quenched byaddition water (30 mL) and extracted with ethyl acetate (20 mL×3). Thecombined organic layers were washed with saturated brine (10 mL×3),dried over Na₂SO₄, filtered, and concentrated under reduced pressure togive 1-10 (0.55 g, 89% yield, 91% purity) as a yellow solid. LCMS (ES⁺):m/z (M+H)⁺=752.2.

Step

11: methyl4′-(6-chloro-1-formyl-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxylate(1-11): To a solution of 1-10 (0.55 g, 0.73 mmol) in HCOOH (16 mL) wasadded saturated aqueous KHSO₄ solution (0.1 g, 0.73 mmol, 43 uL). Themixture was stirred at 25° C. for 1 hr. The reaction mixture wasquenched by addition water 20 mL and extracted with ethyl acetate (10mL×3). The combined organic layers were washed with saturated brine 10mL, dried over Na₂SO₄, filtered, and concentrated under reduced pressureto give 1-11 (0.44 g) as a yellow solid. LCMS (ES⁺): m/z (M+H)⁺=536.2

Step

12: methyl4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′biphenyl]-4-carboxylate(1-12): To a solution of 1-11 (0.44 g, 0.82 mmol) in MeOH (10 mL) wasadded Na₂CO₃ (0.14 g, 1.6 mmol). The mixture was stirred at 25° C. for12 hr to give a yellow methanolic solution of 1-12 (0.40 g, 95.92%yield). The mixture was used for the next step without work-up andpurification. LCMS (ES⁺): m/z m/z (M+H)⁺⁼508.0.

Step 13:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxylicacid (1-13): To a solution of 1-12 (50 mg, 0.79 mmol) in MeOH (2 mL),THF (2 mL) and H₂O (2 mL) was added LiOH·H₂O (7.5 mg, 1.6 mmol). Themixture was stirred at 25° C. for 4 hr. The reaction mixture wasquenched by addition 2N HCl (5 mL), then diluted with ethyl acetate (20mL) and extracted with ethyl acetate (20 mL×2). The combined organiclayers were washed with saturated brine (15 mL×2), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (column: Waters Xbridge C18 150×50mm×10 μm; mobile phase: [A: water (0.225% FA); B: ACN]; B%: 68% - 98%,10 min) and lyophilized to give 1-—(6.05 mg, 11.78% yield, 97.35%purity) as a white solid. LCMS (ES⁺): m/z (M+H)⁺=494.3. ¹H-NMR (DMSO-d₆,400 MHz): δ 8.05 (d, J=8.4 Hz, 2H), 7.93 (s, 1H) 7.87-7.83 (m, 4H),7.78-7.63 (m, 2H), 5.48 (q, J=6.4 Hz, 1H), 4.99 (s, 1H), 4.84 (t, J=5.2Hz, 1H), 4.36 (t, J=4.8 Hz, 1H), 4.14-4.10 (m, 2H), 3.91 (t, J₁=9.6 Hz,J₂=5.6 Hz, 1H), 3.79 (t, J=7.2 Hz, 1H), 3.46-3.42 (m, 1H).

Step 14:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide(Compound 1): To a solution of 1-—(50 mg, 0.10 mmol) in DMF (1 mL) wasadded HATU (46 mg, 0.12 mmol), DIPEA (26 mg, 0.20 mmol, 35 uL), and(2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentaol (18 mg, 0.10 mmol). Themixture was stirred at 25° C. for 12 hr. The reaction mixture wasfiltered to give a solution. The solution was purified by prep-HPLC(column: Phenomenex Synergi C18 150×25 mm×10 μm; mobile phase: [A: water(0.225% FA); B: ACN]; B%: 14%-47%, 10 min) and lyophilized to giveCompound 1 (17.22 mg, 24.88% yield, 96.10% purity) as a white solid.LCMS (ES⁺): m/z (M+H)⁺=657.3. ¹H-NMR (CD₃OD, 400 MHz): δ7.96-7.94 (m,2H), 7.84 (s, 1H), 7.81-7.77 (m, 6H), 5.55 (q, J=5.6 Hz, 1H), 4.97 (t,J=5.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H), 4.30-4.26(m, 1H), 4.18-4.12 (m,2H), 4.02-4.00 (m, 1H), 3.92-3.89 (m, 1H), 3.86-3.84 (m, 1H), 3.82-3.78(m, 1H), 3.74-3.72 (m, 2H), 3.69-3.62 (m, 2H), 3.60-3.49 (m, 2H).

Example 2:(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid (Compound 2)

Step 1:5-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(2-1): To a solution of 1-9 (0.20 g, 0.30 mmol) and(4′-bromo-[1,1′-biphenyl]-4-yl)boronic acid (99 mg, 0.36 mmol) in DME(3.0 mL) and H₂O (0.60 mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (49 mg, 60 μmol)and Na₂CO₃ (95 mg, 0.90 mmol) under N₂. The mixture was stirred at 90°C. for 12 hours. The reaction mixture was quenched by addition water (30mL) and extracted with ethyl acetate (20 mL×3). The combined organiclayers were washed with saturated brine (30 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, petroleum ether :ethyl acetate=20:1 to 10:1) to give 2-1 (0.16 g, 0.19 mmol, 65% yield,94% purity) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.86 (s, 1H),7.83 (m, 2H), 7.64 (m, 2H), 7.59 (m, 2H), 7.53 (m, 2H), 5.55 (m, 3H),4.96 (t, J=10.4 Hz, 1H), 4.43 (t, J=10.0 Hz, 1H), 4.33 (m, 1H), 4.17(dd, J₁=1.2 Hz, J₂=1.2 Hz, 2H), 3.86 (m, 1H), 3.74 (m, 2H), 3.66 (t,J=16.4 Hz, 1H), 0.94 (s, 9H), 0.15 (s, 2H), 0.13 (t, J=6.0 Hz, 6H),−0.64 (s, 9H).

Step 2: di-tert-butyl(4′-(2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonate(2-2): To a solution of 2-1 (0.13 g, 0.17 mmol) and di-tert-butylphosphonate (0.16 g, 0.84 mmol) in THF (4.0 mL) was added KOAc (50 mg,0.50 mmol) and tBu₃P·Pd·G₂ (7.5 mg, 15 μmol) in a glove box. Then themixture was stirred at 65° C. for 16 hours. The reaction mixture wasfiltered to give a residue. The residue was purified by prep-TLC (SiO₂,petroleum ether : ethyl acetate=1:1) to give 2-2 (60 mg, 59 μmmol, 35%yield, 87% purity) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.86 (s,4H), 7.81 (m, 1H), 7.71 (m, 4H), 6.10 (s, 2H), 5.56 (m, 3H), 4.97 (t,J=10.4 Hz, 1H), 4.44 (m, 1H), 4.34 (m, 1H), 4.18 (m, 2H), 3.85 (m, 1H),3.66 (m, 1H), 1.51 (s, 18H), 0.94 (s, 9H), 0.15 (s, 2H), 0.13 (t, J=6.0Hz, 6H), −0.64 (s, 9H).

Step 3:(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid (Compound 2): A solution of 2-2 (55 mg, 54 μmol) in TFA (0.50 mL)was stirred at 25° C. for 3 hours. The reaction mixture was concentratedunder reduced pressure at 25° C. to give a residue. The residue waspurified by prep-HPLC (column: UniSil 3-100 C18 Ultra 150×25 mm×3 μm;mobile phase: [A: water (0.225% FA); B: ACN]; B%: 18%-48%, 10 min) togive Compound 2 (5.4 mg, 17% yield, 96% purity, formic acid salt) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.91 (m, 1H), 7.77 (m, 8H),5.48 (m, 1H), 4.84 (t, J=10.0 Hz, 1H), 4.37 (t, J=9.6 Hz, 1H), 4.14 (m,2H), 3.91 (m, 1H), 3.80 (m, 1H), 3.46 (m, 1H).

Example 3:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide(Compound 3)

Step 1: (2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentayl pentaacetate HClsalt (3-1): To a mixture of (2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentol(1.0 g, 5.5 mmol, 1.0 eq) in AcOH (10 mL) was added acetyl chloride (8.7g, 0.11 mol, 7.9 mL, 20 eq) at 0° C. under N₂. The mixture was stirredat 25° C. for 12 hr. The mixture was concentrated and the residue wastriturated with EtOH and filtered to give 3-1 (1.7 g, 3.9 mmol, 70%yield, HCl salt) as a white solid. ¹NMR (400 MHz, DMSO-d₆) δ 8.17 (br s,3H), 5.34-5.26 (m, 2H), 5.23-5.14 (m, 1H), 5.05-4.96 (m, 1H), 4.23 (dd,J=2.8, 12.4 Hz, 1H), 4.08 (dd, J=6.4, 12.4 Hz, 1H), 3.01 (br s, 2H),2.11 (s, 3H), 2.05 (d, J=8.4 Hz, 6H), 1.99 (d, J=4.4 Hz, 6H).

Step 2: 4′-bromo-[1,1′-biphenyl]-4-sulfonic acid (3-2): To a mixture of1-bromo-4- phenylbenzene (3.0 g, —mmol, 1.0 eq) in CHC—(5 mL) was addedsulfurochloridic acid (1.9 g, 16 mmol, 1.1 mL, 1.3 eq) under N₂. Themixture was stirred at 25° C. for 1 hr. The mixture was concentrated,washed with cold CHCl₃, and filtered to give 3-2 (4.0 g, —mmol, 99%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.70-7.66 (m, 2H),7.66-7.59 (m, 6H).

Step 3: 4′-bromo-[1,1′-biphenyl]-4-sulfonyl chloride (3-3): A solutionof 3-2 (4.0 g, —mmol, 1.0 eq) in SOCl₂ (40 mL) was stirred at 80° C. for2 hr. The mixture was poured into ice water and filtered to give 3-3(3.6 g, 11 mmol, 85% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.71-7.67 (m, 2H), 7.65-7.60 (m, 6H).

Step 4:(2R,3R,4R,5S)-6-(4′-bromo-[1,1′-biphenyl]-4-ylsulfonamido)hexane-1,2,3,4,5-pentaylpentaacetate (3-4): To a solution of 3-3 (1.2 g, 3.7 mmol, 1.0 eq) and3-1 (1.6 g, 3.7 mmol, 1.0 eq, HCl) in DMF (20 mL) was added DIEA (1.9 g,15 mmol, 2.6 mL, 4.0 eq), and the mixture was stirred at 25° C. for 12hr. The mixture was poured into water and extracted with ethyl acetate(100 mL×2). The combined organic phase was washed with brine (100 mL),dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuum. Theresidue was purified by column chromatography (SiO₂, petroleum ether :ethyl acetate=10:1 to 1:1) to give 3-4 (2.4 g, 3.5 mmol, 93% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.01 (s, 1H), 7.94-7.88 (m,2H), 7.86-7.81 (m, 2H), 7.71 (s, 4H), 5.33 (br t, J=6.4 Hz, 2H), 4.97(br d, J=6.0 Hz, 2H), 4.20 (br d, J=11.6 Hz, 1H), 4.05-3.98 (m, 1H),2.97 (br s, 2H), 2.06 (s, 3H), 1.98 (br d, J=8.0 Hz, 12H).

Step 5:(2R,3R,4R,5S)-6-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-ylsulfonamido)hexane-1,2,3,4,5-pentaylpentaacetate (3-5): To a solution of 3-4 (1.5 g, 2.2 mmol, 1.0 eq) andbis(pinacolato)diboron (0.67 g, 2.6 mmol, 1.2 eq) in dioxane (15 mL) wasadded Pd(dppf)Cl₂ (80 mg, 0.11 mmol, 0.050 eq) and KOAc (1.3 g, —mmol,6.0 eq), and the mixture was stirred at 80° C. for 12 hr. The mixturewas poured into water and extracted with ethyl acetate (100 mL×2). Thecombined organic phase was washed with brine (100 mL), dried withanhydrous Na₂SO₄, filtered, and concentrated in vacuum. The residue waspurified by column chromatography (SiO₂, petroleum ether : ethylacetate=10:1 to 1:1) to give 3-5 (1.3 g, 1.8 mmol, 81% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=5.2, 8.4 Hz, 4H), 7.76 (d,J=8.4 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 5.49-5.41 (m, 2H), 5.11-5.00 (m,2H), 4.94 (dd, J=5.2, 8.0 Hz, 1H), 4.29-4.21 (m, 1H), 4.18-4.08 (m, 1H),3.39 (ddd, J=5.6, 8.4, 14.0 Hz, 1H), 3.08 (td, J=5.2, 14.0 Hz, 1H), 2.12(s, 3H), 2.09-2.05 (m, 9H), 2.04 (s, 3H), 1.38 (s, 12H).

Step 6:(2R,3R,4R,5S)-6-(4′-(2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-ylsulfonamido)hexane-1,2,3,4,5-pentaylpentaacetate (3-6): To a solution of 1-9 (0.3 g, 0.45 mmol, 1.0 eq) and3-5 (0.40 g, 0.54 mmol, 1.2 eq) in DME (5.0 mL) and H₂O (1.0 mL) wasadded Na₂CO₃ (0.14 g, 1.4 mmol, 3.0 eq) and Pd(dppf)Cl₂·CH₂Cl₂ (73 mg,90 μmol, 0.20 eq). The mixture was stirred at 90° C. for 1.5 hr. Themixture was filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, petroleum ether : ethyl acetate=100:1 to1:1) to give 3-6 (0.40 g, 0.35 mmol, 78% yield) as a white solid.

Step 7:(2R,3R,4R,5S)-6-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-ylsulfonamido)hexane-1,2,3,4,5-pentaylpentaacetate (3-7): A solution of 3-6 (0.40 g, 0.35 mmol, 1.0 eq) in TFA(10 mL) was stirred at 25° C. for 12 hr. The mixture was concentratedand purified by column chromatography (SiO₂, ethyl acetate :methanol=100:1 to 5:1) to give 3-7 (0.30 g, 0.33 mmol, 95% yield) as awhite solid.

Step 8:4′-(6-chloro-2-(((3R,3aR,6R,6R)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide(Compound 3): To a solution of 3-7 (0.20 g, 0.22 mmol, 1.0 eq) in MeOH(2.0 mL) and H₂O (1.0 mL) was added LiOH·H₂O (56 mg, 1.3 mmol, 6.0 eq),and the mixture was stirred at 25° C. for 3 hr. The mixture wasconcentrated, and the residue was purified by prep-HPLC (column:Phenomenex Luna C18 200×40 mm×10 μm; mobile phase: [A: water (0.2% FA);B: ACN]; B%: 20%-50%, 8 min) to give Compound 3 (50 mg, 32% yield, 99%purity) as a white solid. LCMS (ES⁺): m/z (M+H)⁺=693.2. ¹H NMR (400 MHz,CD₃OD) δ 8.01-7.96 (m, 2H), 7.93-7.88 (m, 2H), 7.80 (s, 5H), 5.55 (br d,J=5.2 Hz, 1H), 4.97 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 4.32-4.25(m, 1H), 4.21-4.08 (m, 2H), 3.90 (t, J=7.6 Hz, 1H), 3.87-3.74 (m, 3H),3.71-3.65 (m, 1H), 3.64-3.57 (m, 3H), 3.16 (dd, J=4.8, 13.2 Hz, 1H),2.97 (dd, J=7.2, 13.2 Hz, 1H).

Example 4:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol(Compound 4)

Step 1: 4′-bromo-[1,1′-biphenyl]-4-carbaldehyde (4-1): To a mixture of1-bromo-4-iodo-benzene (6.0 g, 21 mmol, 1.0 eq), Pd(PPh₃)₄ (1.2 g, 1.1mmol, 0.050 eq), and Na₂CO₃ (2.0 M, 11 mL, 1.0 eq) in toluene (60 mL)was added (4-formylphenyl)boronic acid (3.5 g, 23 mmol, 1.1 eq) inethanol (20 mL) under Ar, and the mixture was stirred at 110° C. for 3hours. The mixture was poured into water and extracted with ethylacetate (100 mL×2). The combined organic phase was washed with brine(100 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated invacuum. The residue was purified by column chromatography (SiO₂,petroleum ether : ethyl acetate=100:1 to 10:1) to give 4-1 (3.0 g, 11mmol, 54% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.07 (s,1H), 7.97 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.8 Hz,2H), 7.54 -7.49 (m, 2H).

Step 2:4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-carbaldehyde(4-2): To a solution of bis(pinacolato)diboron (1.3 g, 5.1 mmol, 1.2 eq)and 4-(4-bromophenyl)benzaldehyde 4-1 (1.1 g, 4.2 mmol, 1.0 eq) indioxane (10 mL) was added Pd(dppf)Cl₂ (0.15 g, 0.21 mmol, 0.050 eq) andKOAc (2.5 g, 25 mmol, 6.0 eq), and the mixture was stirred at 80° C. for12 hr. The mixture was poured into water and extracted with ethylacetate (100 mL×2). The combined organic phase was washed with brine(100 mL), dried with anhydrous Na₂SO₄, filtered, and concentrated invacuum. The residue was purified by column chromatography (SiO₂,petroleum ether : ethyl acetate=100:1 to 10:1) to give 4-2 (1.2 g, 3.9mmol, 92% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.07 (s,1H), 7.97 (br d, J=8.4 Hz, 2H), 7.93 (br d, J=8.0 Hz, 2H), 7.79 (d,J=8.4 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H), 1.38 (s, 12H).

Step 3:4′-(2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carbaldehyde(4-3): To a solution of 4-2 (0.28 g, 0.90 mmol, 1.2 eq) and 1-9 (0.50 g,0.75 mmol, 1.0 eq) in DME (5.0 mL) and H₂O (1.0 mL) was added Na₂CO₃(0.24 g, 2.3 mmol, 3.0 eq) and Pd(dppf)Cl₂·CH₂Cl₂ (0.12 g, 0.15 mmol,0.20 eq) under N₂, and the mixture was stirred at 90° C. for 1.5 hr. Themixture was filtered and concentrated. The residue was purified bycolumn chromatography (SiO₂, petroleum ether : ethyl acetate=100:1 to1:1) to give 4-3 (0.42 g, 0.58 mmol, 78% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 10.09 (s, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.94-7.85 (m,3H), 7.83 (d, J=8.4 Hz, 2H), 7.79-7.69 (m, 2H), 5.64-5.43 (m, 3H), 4.97(t, J=5.2 Hz, 1H), 4.43 (t, J=4.8 Hz, 1H), 4.38-4.29 (m, 1H), 4.18 (d,J=6.0 Hz, 2H), 3.90-3.82 (m, 1H), 3.80-3.72 (m, 2H), 3.67 (t, J=8.4 Hz,1H), 1.02-0.95 (m, 2H), 0.95-0.93 (m, 9H), 0.16-0.13 (m, 6H), 0.07-0.23(m, 9H).

Step 4: (2R,3R,4R,5S)-6-(((4′-(2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol(4-4): To a solution of (2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentol (65mg, 0.36 mmol, 1.3 eq) in AcOH (42 mg, 0.69 mmol, 40 uL, 2.5 eq) andMeOH (2.0 mL) was added a solution of 4-3 (0.20 g, 0.28 mmol, 1.0 eq) inDCM (1.0 mL). After stirring for 1 h, NaBH3CN (35 mg, 0.55 mmol, 2.0 eq)was added, and the mixture was stirred at 25° C. for 12 hr. The mixturewas concentrated and the residue triturated with water to give 4-4 (0.24g) as a white solid.

Step 5:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol(Compound 4): A solution of 4-4 (0.24 g, 0.28 mmol, 1.0 eq) in TFA (5.0mL) was stirred at 25° C. for 1 hr. The mixture was concentrated andpurified by prep-HPLC (column: Phenomenex Luna C18 200×40 mm×10 μm;mobile phase: [A: water (0.2% FA); B: ACN]; B%: 10%-50%, 8 min) to giveCompound 4 (60 mg, 35% yield, formic acid salt) as a white solid. LCMS(ES⁺): m/z (M+H)⁺=643.2. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (s, 1H),7.83-7.78 (m, 1H), 7.83-7.78 (m, 2H), 7.75 (s, 4H), 7.59 (d, J=8.4 Hz,2H), 5.54 (q, J=5.6 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.2 Hz,1H), 4.32-4.23 (m, 3H), 4.19-4.14 (m, 1H), 4.13-4.06 (m, 2H), 3.93-3.87(m, 1H), 3.85 (d, J=3.6 Hz, 1H), 3.77 (dd, J=2.8, 10.6 Hz, 1H),3.72-3.56 (m, 4H), 3.22-3.17 (m, 2H).

Example 5:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-ylcarboxamido)ethanesulfonicacid (Compound 5)

Step 1:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-ylcarboxamido)ethanesulfonicacid (Compound 5): To a solution of 1-—(30 mg, 60 umol, 1 eq) in DMF (1mL) was added 2-aminoethanesulfonic acid (8.4 mg, 67 umol, 8.4 uL, 1.1eq), HATU (35 mg, 91 umol, 1.5 eq) and DIPEA (16 mg, 121 umol, 21 uL, 2eq), and the reaction was stirred at 25° C. for 3 hours. The reactionmixture was filtered. The filter cake was purified by prep-HPLC (column:Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [A: water (0.225%FA); B: ACN]; B%: 20%-50%, 7 min) and lyophilized to give Compound 5 (38mg, 58 umol, 96% yield, 98.11% purity, FA salt) as a yellow oil. LCMS(ES⁺) m/z (M+H)⁺=601.0; HPLC: Rt=1.718 min, 98.11% purity. ¹H NMR (400MHz, DMSO-d₆) δ 8.59 (t, J=5.2 Hz, 1H), 7.95 (s, 1H), 7.90 (s, 2H),7.87-7.82 (m, 4H), 7.79 -7.75 (m, 2H), 5.54-5.45 (m, 1H), 4.84 (t, J=5.2Hz, 1H), 4.36 (t, J=4.8 Hz, 1H), 4.17-4.10 (m, 2H), 3.95-3.88 (m, 2H),3.81-3.77 (m, 2H), 3.582-3.534 (m, 2H), 3.45 (br d, J=8.8 Hz, 2H), 2.71(t, J=7.2 Hz, 2H).

Example 6:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonicacid (Compound 6)

Compound 6 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁺) m/z (M+H)⁺=615.1; ¹H NMR (400 MHz, DMSO-d₆) δ8.77-8.68 (m, 1H), 7.96 (s, 3H), 7.88-7.80 (m, 4H), 7.78 (s, 2H),5.52-5.45 (m, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.36 (t, J=4.8 Hz, 1H),4.19-4.08 (m, 2H), 3.96-3.88 (m, 1H), 3.79 (t, J=7.2 Hz, 1H), 3.46-3.42(m, 3H), 3.370-3.339 (m, 3H), 2.56-2.52 (m, 2H), 1.90-1.82 (m, 2H).

Example 7:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)-2-(4-chlorophenyl)propane-1-sulfonicacid (Compound 7)

Compound 7 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁻) m/z (M-H)⁻=723.0; ¹H NMR (400 MHz, DMSO-d₆) δ9.00-8.93 (m, 1H), 7.97-7.87 (m, 3H), 7.85-7.79 (m, 4H), 7.78-7.73 (m,2H), 7.34-7.26 (m, 4H), 5.53-5.44 (m, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.36(t, J=4.8 Hz, 1H), 4.18-4.09 (m, 2H), 3.96-3.89 (m, 1H), 3.79 (t, J=7.2Hz, 1H), 3.70-3.52 (m, 3H), 3.46-3.41 (m, 4H), 3.11-2.99 (m, 1H),2.79-2.70 (m, 1H).

Example 8:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]4-carboxamido)ethane-1-sulfonicacid (Compound 8)

Compound 8 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁺) m/z (M+H)⁺=615.3. ¹H NMR (400 MHz, DMSO-d₆) δ 7.94(s, 1H), 7.84-7.74 (m, 6H), 7.51 (s, 2H), 5.48 (q, J=6.0 Hz, 1H), 4.99(d, J=2.8 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H), 4.36 (t, J=4.8 Hz, 1H), 4.12(dd, J₁=9.6 Hz, J₂=6.0 Hz, 2H), 3.91 (dd, J₁=9.6 Hz, J₂=6.0 Hz, 1H),3.79 (t, J=7.2 Hz, 1H), 3.74-3.60 (m, 1H), 3.53 (d, J=8.8 Hz, 1H),3.46-3.40 (m, 1H), 2.96 (s, 3H), 2.82 -2.68 (m, 2H).

Example 9:2-(N-(2-amino-2-oxoethyl)-4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid (Compound 9)

Compound 9 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁺) m/z (M+H)⁺=679.4. ¹H NMR (400 MHz, CD₃OD) δ 7.90(br s, 1H), 7.76 (br s, 6H), 7.65 (br d, J=7.2 Hz, 1H), 7.57 (br d,J=7.6 Hz, 1H), 5.60-5.53 (m, 1H), 4.97 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.8Hz, 1H), 4.32-4.22 (m, 2H), 4.20-4.08 (m, 3H), 3.96-3.81 (m, 3H), 3.60(t, J=8.4 Hz, 1H), 3.26 (br t, J=6.0 Hz, 1H), 3.19-3.04 (m, 1H).

Example 10:5-((2′-(6-chloro-2(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)amino)naphthalene-1-sulfonicacid (Compound 10)

Compound 10 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁺) m/z (M+H)⁺=742.3. ¹H NMR (400 MHz, CD₃OD) δ8.24-8.11 (m, 3H), 7.98-7.91 (m, 2H), 7.83-7.74 (m, 7H), 7.42 (t, J=8.0Hz, 2H), 6.82-6.73 (m, 1H), 5.58-5.49 (m, 1H), 4.96 (br t, J=4.8 Hz,1H), 4.49-4.43 (m, 1H), 4.31-4.24 (m, 1H), 4.20-4.13 (m, 1H), 4.13-4.07(m, 1H), 3.90 (t, J=7.6 Hz, 1H), 3.83-3.76 (m, 2H), 3.63-3.52 (m, 3H).

Example 11:4-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)benzenesulfonicacid (Compound 11)

Compound 11 is synthesized using methods analogous to those described inExample 5. LCMS (ES⁺) m/z (M+H)⁺=677.0. ¹H NMR (400 MHz, CD₃OD) δ7.91-7.85 (m, 2H), 7.84 (s, 1H), 7.81-7.74 (m, 8H), 7.35 (d, J=8.4 Hz,2H), 5.58-5.51 (m, 1H), 4.97 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H),4.32-4.25 (m, 1H), 4.20-4.14 (m, 1H), 4.14-4.08 (m, 1H), 3.94-3.87 (m,1H), 3.69-3.57 (m, 3H), 3.00 (t, J=7.2 Hz, 2H).

Example 12:(4′-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid (Compound 12)

Step 1:6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(12-1): To a solution of2-[(6-chloro-5-iodo-2-methylsulfonyl-imidazo[4,5-b]pyridin-1-yl)methoxy]ethyl-trimethyl-silane(1.8 g, 3.69 mmol, 1 eq) and(4aR,7R,8aS)-2-phenyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-7-ol(1.05 g, 4.4 mmol, 1.2 eq) in DMF (18 mL) was added Cs₂CO₃ (2.4 g, 7.4mmol, 2 eq). The mixture was stirred at 25° C. for 12 hours. Thereaction mixture was partitioned between EA (100 mL) and water (10 mL).The organic phase was separated, washed with brine (25 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate, 100/1 to 10/1 gradient) to give 12-1 (1.8g, 76% yield) as a yellow solid. LCMS (ES+) m/z (M+H)⁺=644.0.

Step 2:5-(4′-bromo-[1,1′-biphenyl]-4-yl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(12-2): To a solution of 12-1 (100 mg, 155 umol, 1 eq) and[4-(4-bromophenyl)phenyl]boronic acid (47 mg, 171 umol, 1.1 eq) in DME(1.6 mL) and H₂O (0.4 mL) was added Pd(dppf)Cl₂ (6 mg, 7.8 umol, 0.05eq) and Na₂CO₃ (33 mg, 311 umol, 2 eq). The mixture was stirred at 90°C. for 2 hours. The mixture was poured into 10 mL of H₂O and extractedwith EA (10 mL×3). The combined organic layer was washed with water (10mL×2) and brine (10 mL×2), dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash silica gel chromatography (ISCO®; 4 gSepaFlash® Silica Flash Column, Eluent of 0% to 10% MeOH/DCM @ 20mL/min) to give 12-2 (80 mg, 63% yield, 92% purity) as a yellow solid.LCMS (ES+) m/z (M+H)⁺=750.0. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H),7.85-7.81 (m, 2H), 7.67-7.63 (m, 2H), 7.62-7.58 (m, 2H), 7.55-7.49 (m,4H), 7.42-7.36 (m, 3H), 5.59 (s, 1H), 5.49 (s, 2H), 5.46-5.38 (m, 1H),4.48-4.33 (m, 2H), 3.79-3.67 (m, 4H), 3.57-3.49 (m, 1H), 3.47-3.38 (m,1H), 2.97-2.85 (m, 1H), 2.03-1.91 (m, 1H), 0.99-0.91 (m, 2H), −0.01-0.08(m, 9H).

Step 3: di-tert-butyl(4′-(6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonate(12-3): To a mixture of 12-2 (80 mg, 107 umol, 1 eq) and2-tert-butoxyphosphonoyloxy-2-methyl-propane (104 mg, 534 umol, 5 eq) inTHF (1 mL) was added KOAc (31 mg, 320 umol, 3 eq) and tBu₃P·Pd·G₂ (6 mg,11 umol, 0.1 eq) in a glovebox. Then the mixture was stirred at 65° C.for 12 hours. The reaction mixture was filtered, and the filtrate wasconcentrated. The residue was purified by flash silica gelchromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0%to 50% Ethyl acetate/Petroleum ether gradient @ 12 mL/min) to give 12-3(65 mg, 64% yield, 91% purity) as a colorless oil. LCMS (ES+) m/z(M+H)⁺=862.5.

Step 4: (4′-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid (Compound 12): A mixture of 12-3 (60 mg, 70 umol, 1 eq) inHCl/dioxane (4 M, 522 uL, 30 eq) was stirred at 25° C. for 2 hours. Themixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150×25 mm×10 um; mobile phase: [water(0.225% FA); B: ACN]; B%: 9%-39%, 10 min) and lyophilized to giveCompound 12 (8.52 mg, 22% yield, 95% purity, FA salt) as a white solid.LCMS (ES+) m/z (M+H)⁺=532.2. ¹H NMR (400 MHz, CD₃OD) δ 7.97-7.89 (m,2H), 7.84 (s, 1H), 7.82-7.74 (m, 6H), 5.21-5.09 (m, 1H), 4.41-4.33 (m,1H), 3.94-3.88 (m, 1H), 3.71-3.60 (m, 2H), 3.42-3.36 (m, 1H), 3.22-3.14(m, 1H), 2.83-2.73 (m, 1H), 1.80-1.65 (m, 1H).

Example 13:(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)phosphonicacid (Compound 14)

To a solution of 1-—(0.10 g, 0.2 mmol) in H₂O (2 mL) and DMSO (2 mL) wasadded (3-aminopropyl)phosphonic acid (56 mg, 0.41 mmol) and DMTMM (0.17g, 0.61 mmol). The mixture was stirred at 80° C. for 48 hours. Thereaction mixture was purified by prep-HPLC (column: Phenomenex SynergiC18 150×25 mm×10 um; mobile phase: [A: water (0.225% FA), B: ACN]; B%:25%-55%) and further purified by prep-HPLC (column: 3_Phenomenex LunaC18 75×30 mm×3 um; mobile phase: [A: water (0.05% HCl), B: ACN]; B%:19%-39%) to give Compound 14 (5.5 mg, 4% yield) as a white solid. LCMS:(ES+) m/z (M+H)+=615.2. ¹H NMR (400 MHz, CD₃OD) δ=8.15 (s, 1H), 7.96 (d,J=8.4 Hz, 2H), 7.89-7.83 (m, 3H), 7.83-7.75 (m, 3H), 5.62 (q, J=5.2 Hz,1H), 4.98 (t, J=5.4 Hz, 1H), 4.47 (t, J=5.0 Hz, 1H), 4.34-4.24 (m, 1H),4.22-4.09 (m, 2H), 3.93-3.85 (m, 1H), 3.59 (t, J=8.6 Hz, 1H), 3.50 (t,J=6.8 Hz, 2H), 2.02-1.89 (m, 2H), 1.87-1.74 (m, 2H).

Example 14:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)-N,N,N-trimethylethan-1-aminiumbicarbonate (Compound 29)

14-1 was synthesized using methods analogous to those described inExample 1, for Compound 1-13. LCMS: (ES+) m/z (M+H)⁺=493.2.; ¹H NMR (400MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.45-7.29 (m,2H), 5.44 (q, J=6.0 Hz, 1H), 4.98 (s, 1H), 4.83 (t, J=4.8 Hz, 1H), 4.36(t, J=4.8 Hz, 1H), 4.14-4.10 (m, 2H), 3.90-3.87 (m, 1H), 3.79 (t, J=7.6Hz, 1H), 3.44 (t, J=8.8 Hz, 1H).

To a solution of 14-1 (50 mg, 0.10 mmol, 1 eq) in DMF (1 mL) was addedHATU (77 mg, 0.20 mmol, 2 eq), DIEA (26 mg, 0.20 mmol, 35uL, 2 eq) and2-aminoethyl (trimethyl)ammonium chloride hydrochloride (36 mg, 0.20mmol, 2 eq). The mixture was stirred at 25° C. for 12 hours. Thereaction mixture was purified by prep-HPLC (column: Phenomenex Gemini-NXC18 75×30 mm×3 um; mobile phase: [A: water (10 mMNH₄HCO₃), B: ACN]; B%:12%-42%) to give Compound 29 (bicarbonate salt, 21 mg, 34% yield) as awhite solid. LCMS: (ES+) m/z (M)+=577.2. ¹H-NMR (400 MHz, CD₃OD) δ=7.95(d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.54(d, J=8.4 Hz, 2H), 7.46 (s, 1H), 7.32 (s, 1H), 5.50-5.40 (m, 1H),4.96-4.93 (m, 3H), 4.47 (t, J=4.8 Hz, 1H), 4.33-4.25 (m, 1H), 4.20-4.13(m, 1H), 4.10-7.05 (m, 1H), 3.91 (s, 3H), 3.64-3.58 (m, 3H), 3.26 (s,9H).

Example 15:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide(Compound 30)

Compound 30 is synthesized using methods analogous to those described inExample 14. LCMS: (ES+) m/z (M+H)+=656.1. ¹H NMR (400 MHz, CD₃OD) δ 7.95(d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H), 7.54(d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.33 (s, 1H), 5.44 (q, J=5.2 Hz, 1H),4.95-4.93 (m, 2H), 4.47 (t, J=4.8 Hz, 1H), 4.31-4.24 (m, 1H), 4.20-4.14(m, 1H), 4.13-4.07 (m, 1H), 4.06-3.97 (m, 1H), 3.95-3.87 (m, 1H),3.86-3.76 (m, 2H), 3.75-3.58 (m, 5H). 3.55-3.45 (m, 1H).

Example 16:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide(Compound 31)

Compound 31 was synthesized using methods analogous to those describedin Example 14. LCMS: (ES+) m/z (M)+=580.2. ¹H NMR (400 MHz, CD₃OD)δ=7.94 (d, J=8.0 Hz, 2H), 7.83-7.69 (m, 4H), 7.57-7.50 (m, 2H), 7.47 (s,1H), 7.32 (d, J=3.2 Hz, 1H), 5.50-5.40 (m, 1H), 4.95 (t, J=5.6 Hz, H),4.47 (t, J=5.2 Hz, 1H), 4.33-4.25 (m, 1H), 4.20-4.12 (m, 1H), 4.11-4.04(m, 1H), 3.91 (t, J=7.5 Hz, 1H), 3.73-3.66 (m, 4H), 3.65-3.57 (m, 5H).

Example 17:1-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)-1,4-diazabicyclo[2.2.2]octan-1-iumformate (Compound 32)

Compound 32 was synthesized as the formate salt using methods analogousto those described in Example 14. LCMS: (ES+) m/z (M+H)+=719.4. ¹H NMR(400 MHz, DMSO-d₆) δ=8.98 (br s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.89 (d,J=8.4 Hz, 2H), 7.87-7.77 (m, 5H), 5.51 (q, J=6.3 Hz, 1H), 4.85 (t, J=5.0Hz, 1H), 4.53 (s, 2H), 4.42 (t, J=4.9 Hz, 1H), 4.24-4.15 (m, 2H), 3.93(dd, J=6.4, 9.4 Hz, 1H), 3.86-3.74 (m, 6H), 3.51 (t, J=8.4 Hz, 1H), 3.36(br s, 4H), 2.78-2.70 (m, 3H), 2.18-2.05 (m, 2H).

Example 18:1-(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-iumtrifluoroacetate (Compound 33)

Compound 33 was synthesized as the trifluoroacetate salt using methodsanalogous to those described in Example 14. LCMS: (ES+) m/z(M+H)+=644.3. 1H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=8.4 Hz, 2H), 7.82 (d,J=8.4 Hz, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.57-7.51 (m, 3H), 7.39 (s, 1H),5.51-5.43 (m, 1H), 4.98 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H),4.32-4.24 (m, 1H), 4.15 (m, 2H), 3.95-3.85 (m, 1H), 3.59 (t, J=8.4 Hz,1H), 3.55-3.50 (m, 2H), 3.49-3.42 (m, 6H), 3.42-3.36 (m, 2H), 3.30-3.23(m, 6H), 2.20-2.07 (m, 2H).

Example 20:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-carboxamide(Compound 48)

Compound 48 was synthesized using methods analogous to those describedin Example 14. LCMS: (ES+) m/z (M)+=594.5. ¹H NMR (400 MHz, CD₃OD)δ=7.82-7.69 (m, 4H), 7.60-7.51 (m, 4H), 7.49 (s, 1H), 7.34 (s, 1H), 5.46(q, J=5.4 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.0 Hz, 1H),4.32-4.25 (m, 1H), 4.13 (qd, J=10.2, 5.2 Hz, 2H), 3.91 (dd, J=8.2, 6.8Hz, 1H), 3.79 (br s, 2H), 3.74-3.55 (m, 6H), 3.50 (br s, 1H), 3.14 (brd, J=6.88 Hz, 3H).

Example 21:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carbaldehyde(Intermediate 21-1)

Step 1: A solution of 4-3 (2.3 g, 3.2 mmol, 1 eq) in TFA (23 mL) wasstirred at 25° C. for 3 hrs. The mixture was concentrated in vacuo togive a residue. The residue was purified by prep- HPLC (column:Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (0.225%FA)-ACN]; B%: 30%-60%, 11 min) to give intermediate 21-1 (0.84 g, 50%yield) as a white solid. LCMS: (ES+) m/z (M+H)+=478.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.08 (s, 1H), 8.05-7.86 (m, 7H), 7.81-7.79 (m, 2H),5.51-5.46 (m, 1H), 4.99 (d, J=6.8 Hz, 1H), 4.84 (t, J=4.8 Hz, 1H), 4.36(t, J=4.8 Hz, 1H), 4.18-4.09 (m, 2H), 3.94-3.90 (m, 1H), 3.81-3.77 (m,1H), 3.44 (t, J=4.4 Hz, 1H).

Example 22:3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-hydroxypropanoicacid (Compound 22)

Step 1: To a solution of 21-1 (50 mg, 0.11 mmol) and3-amino-2-hydroxypropanoic acid (14 mg, 0.14 mmol) in DMF (0.5 mL) wasadded AcOH (31 mg, 0.52 mmol). The mixture was stirred at 25° C. for 12hrs. Then NaBH(OAc)₃ (33 mg, 0.16 mmol) was added. The mixture wasstirred at 25° C. for another 12 hrs. The mixture was filter, and theorganic phase was collected and then purified by prep-HPLC (column:Shim-pack C18 150×25×10 um; mobile phase: [A: water (0.225% FA), B:ACN];B%: 16% -36%) to give Compound 22 (30 mg, 48% yield) as a white solid.LCMS: (ES+) m/z (M+H)+=567.2. ¹H NMR (400 MHz, CD₃OD) δ=8.34 (s, 1H),7.82 (br d, J=2.4 Hz, 2H), 7.80 (s, 1H), 7.75 (s, 4H), 7.61 (br d, J=8.0Hz, 2H), 5.55 (br d, J=5.4 Hz, 1H), 4.97 (t, J=5.0 Hz, 2H), 4.47 (t,J=4.8 Hz, 1H), 4.33-4.26 (m, 3H), 4.18-4.09 (m, 3H), 3.90 (dd, J=7.0,8.4 Hz, 1H), 3.60 (t, J=8.6 Hz, 1H), 3.13 (dd, J=8.2, 12.4 Hz, 1H).

Example 23:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 49)

23-1 was synthesized using methods analogous to those described inExamples 4 and 21. LCMS: (ES+) m/z (M+H)+=477.0. ¹H NMR (400 MHz,DMSO-d₆) δ 10.07 (s, 1H), 8.04-7.98 (m, 4H), 7.86 (d, J=8.4 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 7.45-7.32 (m, 2H), 5.44 (q, J=6.0 Hz, 1H), 4.99(d, J=4.8 Hz, 1H), 4.83 (t, J=5.2 Hz, 1H), 4.36 (t, J=5.2 Hz, 1H),4.14-4.10 (m, 2H), 3.90-3.87 (m, 1H), 3.79 (t, J=7.2 Hz, 1H), 3.44 (t,J=8.4 Hz, 1H).

Step 1: A mixture of 23-1 (0.30 g, 0.63 mmol), tert-butylpiperazine-1-carboxylate (0.12 g, 0.63 mmol), AcOH (0.11 g, 1.9 mmol)and 4 Å MS (0.5 g) in THF (5 mL) and DMSO (1 mL) was stirred at 40° C.for 1 hr. Then to the mixture was added NaBH(OAc)₃ (0.27 g, 1.3 mmol),and the mixture was stirred at 25° C. for 6 hrs. The reaction mixturewas quenched by addition of saturated aqueous NH₄Cl (20 mL) and thenextracted with THF (20 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give tert-butyl4-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate(0.40 g, crude) as yellow solid. LCMS: (ES+) m/z (M+H)+=647.2.

Step 2: A mixture of tert-butyl4-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate(0.40 g, 0.46 mol) and TFA (3 mL) was stirred at 25° C. for 1 hr. Thereaction mixture was concentrated under vacuum to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Gemini 150×25mm×10 um; mobile phase: [A: water (0.225% FA), B: ACN]; B%: 5%-35%) togive Compound 49 (0.16 g, 60% yield) as an off-white solid. LCMS: (ES+)m/z (M+H)+=547.4. ¹H NMR (400 MHz, CD₃OD) δ=8.52 (s, 1H), 7.68 (d, J=8.0Hz, 4H), 7.57-7.39 (m, 5H), 7.32 (s, 1H), 5.45 (q, J=5.2 Hz, 1H), 4.95(t, J=5.2 Hz, 1H), 4.47 (t,

J=5.2 Hz, 1H), 4.28 (ddd, J=5.2, 6.8, 8.8 Hz, 1H), 4.20-4.13 (m, 1H),4.11-4.03 (m, 1H), 3.91 (dd, J=6.9, 8.0 Hz, 1H), 3.67 (s, 2H), 3.61 (t,J=8.8 Hz, 1H), 3.26-3.16 (m, 4H), 2.72 (br d, J=4.4 Hz, 4H).

Example 24:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 50)

Step 1: To a solution of (1-benzhydrylazetidin-3-yl)methanol (2.5 g, 9.9mmol, 1 eq) in THF (25 mL) was added NaH (0.79 g, 20 mmol, 60% purity, 2eq) in portions at 0° C. The mixture was stirred at 0° C. for 1 hr. Then2-bromoethoxymethylbenzene (2.4 g, 11 mmol, 1.8 mL, 1.1 eq) was addeddropwise at 0° C. The mixture was stirred at 25° C. for 2 hrs. Theresidue was quenched by water (20 mL), then extracted with EA (50 mL×3).The combined organic layers were washed with saturated brine (30 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 1/1) to give24-1 (1.6 g, 41% yield) as a yellow oil. LCMS: (ES+) m/z (M+H)+=388.3.¹H NMR (400 MHz, CDCl₃) δ 7.35-7.30 (m. 1H), 7.33 (d, J=7.2 Hz, 3H),7.27 (br d, J=3.24 Hz, 3H), 7.23-7.16 (m, 5H), 7.15-7.07 (m, 3H), 4.50(s, 2H), 4.29-4.25 (m, 1H), 3.58-3.51 (m, 6H), 3.28-3.16 (m, 2H),2.90-2.76 (m, 2H), 2.73-2.59 (m, 1H).

Step 2: To a solution of 24-1 (1.6 g, 4.1 mmol, 1 eq) in MeOH (16 mL)was added 20% Pd(OH)₂/C (1.0 g) under N₂. The suspension was degassedunder vacuum and purged with H2 several times. The mixture was stirredunder H₂ (50 psi) at 40° C. for 4 hours. The reaction mixture wasfiltered and concentrated under reduced pressure to give 24-2 (0.75 g,crude) as a gray oil. ¹H NMR (400 MHz, CD₃OD) δ 3.72-3.65 (m, 4H),3.62-3.58 (m, 2H), 3.57-3.51 (m, 3H), 3.49-3.42 (m, 2H), 3.01-2.85 (m,1H).

Step 3: A mixture of 23-1 (0.45 g, 0.94 mmol, 1 eq), 24-2 (0.25 g, 1.9mmol, 2 eq), and AcOH (0.17 g, 2.8 mmol, 3 eq) in THF (2.5 mL) and DMSO(2.5 mL) was stirred at 40° C. for 1.5 hrs. Then to the mixture wasadded NaBH(OAc)₃ (0.60 g, 2.8 mmol, 3 eq), and the mixture stirred at25° C. for 12 hrs. The reaction mixture was quenched by addition ofwater (5 mL) and then purified by prep-HPLC (column: YMC Triart C18250×50 mm×7 um; mobile phase: [A: water (10 mM NH₄HCO₃), B: ACN]; B%:31%-61%) to give Compound 50 (0.17 g, 29% yield) as a white solid. LCMS:(ES+) m/z (M+H)+=592.1. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (d, J=8.0 Hz,2H), 7.66 (d, J=8.0 Hz, 2H), 7.53-7.46 (m, 3H), 7.39-7.33 (m, 2H),7.31-7.27 (m, 1H), 5.43 (q, J=6.0 Hz, 1H), 5.01-4.93 (m, 1H), 4.82 (t,J=4.8 Hz,1H), 4.70-4.45 (m, 1H), 4.36 (t, J=4.8 Hz, 1H), 4.13-4.11 (m,2H), 3.89-3.87 (m, 1H), 3.79 (t, J=7.6 Hz, 1H), 3.58-3.53 (m, 4H),3.49-3.47 (m, 2H), 3.44-3.39 (m, 4H), 3.29-3.24 (m, 4H), 2.91 (t, J=6.4Hz, 2H), 2.63-2.57 (m, 1H).

Example 25:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 51)

Compound 51 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=592.2. ¹H NMR (400 MHz, DMSO-d₆) δ13.36-12.09 (m, 1H), 7.93 (s, 1H), 7.83-7.62 (m, 6H), 7.40 (d, J=8.1 Hz,2H), 5.48 (q, J=5.9 Hz, 1H), 4.99 (br d, J=6.6 Hz, 1H), 4.84 (t, J=5.0Hz, 1H), 4.36 (br t, J=4.8 Hz, 2H), 4.23-4.07 (m, 2H), 3.91 (dd, J=5.9,9.5 Hz, 1H), 3.79 (t, J=7.4 Hz, 1H), 3.57-3.39 (m, 6H), 2.47-2.31 (m,9H).

Example 26:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol(Compound 52)

Compound 52 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=579.2. ¹H NMR (400 MHz, CD₃OD)δ=7.80 (s, 1H), 7.76-7.63 (m, 6H), 7.42 (d, J=8.3 Hz, 2H), 5.53 (q,J=5.5 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.9 Hz, 1H), 4.28(ddd, J=5.2, 6.7, 8.7 Hz, 1H), 4.22-4.04 (m, 2H), 3.90 (dd, J=6.8, 8.2Hz, 1H), 3.78 (s, 2H), 3.69 (s, 4H), 3.60 (t, J=8.6 Hz, 1H), 3.25 (s,4H).

Example 27:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol(Compound 53)

Compound 53 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=583.0. ¹H NMR (400 MHz, CD₃OD) δ7.85-7.71 (m, 7H), 7.61 (d, J=8.4 Hz, 2H), 5.60-5.49 (m, 1H), 4.96 (t,J=5.2 Hz, 1H), 4.71 (t, J=5.2 Hz, 1H), 4.33-4.24 (m, 3H), 4.20-4.14 (m,1H), 4.14-4.07 (m, 1H), 3.94-3.87 (m, 1H), 3.80 (s, 6H), 3.60 (t, J=8.8Hz, 1H).

Example 28:(1((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol(Compound 54)

Compound 54 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=607.0. ¹H NMR (400 MHz, CD₃OD) δ8.50 (br s, 1H), 7.84-7.78 (m, 3H), 7.76 (s, 4H), 7.57 (d, J=8.4 Hz,2H), 5.55 (q, J=5.2 Hz, 1H), 4.97 (t, J=4.8 Hz, 1H), 4.47 (t, J=5.2 Hz,1H), 4.32-4.26 (m, 1H), 4.19-4.15 (m, 3H), 4.13-4.09 (m, 1H), 3.90 (dd,J=7.2, 8.4 Hz, 1H), 3.60 (t, J=8.4 Hz, 1H), 3.55-3.48 (m, 4H), 3.15-3.05(m, 4H), 1.73 (br t, J=5.6 Hz, 4H)

Example 29:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′((4-(hydroxymethyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 55)

Compound 55 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=576.1. ¹H NMR (400 MHz, CD₃OD) δ7.72-7.61 (m, 4H), 7.56 -7.40 (m, 5H), 7.32 (s, 1H), 5.45 (q, J=5.6 Hz,1H), 4.94 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.0 Hz, 1H), 4.28 (ddd, J=5.2,6.8, 8.8 Hz, 1H), 4.21-4.11 (m, 1H), 4.11-4.04 (m, 1H), 3.91 (dd, J=6.8,8 Hz, 1H), 3.65-3.56 (m, 3H), 3.40 (d, J=6.4 Hz, 2H), 2.98 (br d, J=11.6Hz, 2H), 2.14-2.03 (m, 2H), 1.75 (br d, J=12.4 Hz, 2H), 1.55-1.42 (m,1H), 1.36-1.23 (m, 2H).

Example 30:(3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 56)

Compound 56 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=591.1. ¹H NMR (400 MHz, DMSO-d₆)δ=7.73 (d, J=8.4 Hz 2H), 7.68 (d, J=8.4 Hz 2H), 7.51 (d, J=8.4 Hz 2H),7.35 (d, J=8.4 Hz, 2H), 7.34-7.25 (m, 2H), 5.43 (q, J=6.0 Hz, 1H), 5.00(d, J=6.8 Hz, 1H), 4.83 (t, J=5.2 Hz, 1H), 4.39-4.36 (m, 2H), 4.14-4.10(m, 2H), 3.90-3.79 (m, 2H), 3.50-3.32 (m, 5H), 2.52-2.27 (m, 9H).

Example 31:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 57)

Compound 57 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=561.4. ¹H NMR (400 MHz, CD₃OD) δ7.67 (t, J=8 Hz, 4H), 7.52 -7.42 (m, 5H), 7.32 (s, 1H), 5.45 (q, J=5.2Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 4.28 (ddd,J=5.2, 6.8, 8.8 Hz, 1H), 4.19-4.14 (m, 1H), 4.11-4.05 (m, 1H), 3.91 (dd,J=6.8, 8.0 Hz, 1H), 3.63-3.57 (m, 3H), 2.82-2.34 (m, 8H), 2.30 (s, 3H).

Example 32:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 58)

Compound 58 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=566.4. ¹H NMR (400 MHz, CD₃OD) δ7.68 (dd, J=8.2, 2.4 Hz, 4 H), 7.54-7.43 (m, 5H), 7.32 (s, 1H), 5.45 (q,J=5.6 Hz, 1H), 4.98-4.94 (m, 1H), 4.47 (t, J=5.0 Hz, 1H), 4.33-4.25 (m,1H), 4.20-4.13 (m, 1H), 4.11-4.05 (m, 1H), 3.91 (t, J=7.4 Hz, 1H), 3.86(s, 2H), 3.71-3.66 (m, 2H), 3.66-3.62 (m, 2H), 3.61 (s, 1H), 3.57-3.52(m, 2H), 2.84 (t, J=5.2 Hz, 2H).

Example 33:(R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidin-3-ol(Compound 59)

Compound 59 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=548.0. ¹H NMR (400 MHz, CD₃OD)δ=7.67 (t, J=8.0 Hz, 4H), 7.56-7.42 (m, 5H), 7.32 (s, 1H), 5.45 (q,J=5.6 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.0 Hz, 1H), 4.40-4.34(m, 1H), 4.32-4.24 (m, 1H), 4.20-4.03 (m, 2H), 3.91 (dd, J=8.2, 6.8 Hz,1H), 3.78-3.55 (m, 3H), 2.92-2.73 (m, 2H), 2.65-2.49 (m, 2H), 2.26-2.07(m, 1H), 1.76 -1.74 (m, 1H).

Example 34:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol(Compound 60)

Compound 60 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=606.2. ¹H NMR (400 MHz, CD₃OD) δ7.67 (t, J=8.0 Hz, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.46 (s, 1H), 7.43 (d,J=8.0 Hz, 2H), 7.32 (s, 1H), 5.45 (q, J=5.6 Hz, 1H), 4.94 (t, J=5.2 Hz,1H), 4.47 (t, J=5.0 Hz, 1H), 4.28 (ddd, J=5.3, 6.8, 8.8 Hz, 1H),4.20-4.04 (m, 2H), 3.91 (dd, J=6.8, 8.2 Hz, 1H), 3.66-3.56 (m, 3H), 3.49(s, 4H), 2.51 (br t, J=5.6 Hz, 4H), 1.54 (br t, J=5.6 Hz, 4H).

Example 35:(3S,4R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol(Compound 61)

Compound 61 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=564.1. ¹H NMR (400 MHz, CD₃OD) δ7.75-7.62 (m, 4H), 7.60 -7.42 (m, 5H), 7.32 (br d, J=2.4 Hz, 1H), 5.45(q, J=5.2 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H),4.29-4.27 (m, 1H), 4.20-4.12 (m, 3H), 4.11-4.05 (m, 1H), 3.91 (dd,J=8.4, 6.8 Hz, 1H), 3.75 (s, 2H), 3.61 (t, J=8.6 Hz, 1H), 3.02-2.99 (m,2H), 2.67-2.57 (m, 2H).

Example 36:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)(methyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzoldlimidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 62)

Compound 62 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=580.5. ¹H NMR (400 MHz, CD₃OD) δ8.50 (s, 1H) 7.79 (br d, J=8.0 Hz, 2H) 7.72 (br d, J=8.0 Hz, 2H) 7.58(br d, J=8.0 Hz, 2H) 7.53 (br d, J=8.0 Hz, 2H) 7.47 (br s, 1H) 7.32 (brs, 1H) 5.45 (q, J=5.2 Hz, 1H) 4.95 (br t, J=5.2 Hz, 1H) 4.47 (br t,J=4.8 Hz, 1H) 4.33-4.21 (m, 3H) 4.19-4.13 (m, 1H) 4.12-4.06 (m, 1H) 3.91(br t, J=7.6 Hz, 1H) 3.85-3.78 (m, 2H) 3.76-3.70 (m, 2H) 3.65-3.56 (m,3H) 3.28-3.15 (m, 2H) 2.84-2.66 (m, 3H).

Example 37:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′((3-(hydroxymethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 63)

Compound 62 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M)+=548.1. ¹H NMR (400 MHz, CD₃OD) δ7.70-7.64 (m, 4H), 7.50 (d, J=8.4 Hz, 2H), 7.46 (s, 1H), 7.40 (d, J=8.0Hz, 2H), 7.32 (s, 1H), 5.45 (q, J=5.6 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H),4.47 (t, J=4.9 Hz, 1H), 4.29-4.27 (m, 1H), 4.19-4.14 (m, 1H), 4.11-4.06(m, 1H), 3.91 (dd, J=7.2, 8.8 Hz, 1H), 3.71 (s, 2H), 3.66 (d, J=6.4 Hz,2H), 3.60 (t, J=8.4 Hz, 1H), 3.46 (t, J=8.0 Hz, 2H), 3.18-3.11 (m, 2H),2.74-2.67 (m, 1H).

Example 38:(3S,4S)-1-((4′-(6-chloro-2-(43R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol(Compound 64)

Compound 64 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=564.4. ¹H NMR (400 MHz, DMSO-d₆)δ=12.24 (br s, 1H) 7.74 (d, J=8.4 Hz, 2H) 7.68 (d, J=8.4 Hz, 2H) 7.51(d, J=8.4 Hz, 3H) 7.41 (d, J=8.4 Hz, 2H) 7.19-7.37 (m, 1H) 5.44 (q,J=6.0 Hz, 1H) 4.97 (d, J=6.8 Hz, 1H) 4.80-4.87 (m, 3H) 4.37 (t, J=4.8Hz, 1H) 4.09 -4.20 (m, 2H) 3.84-3.92 (m, 3H) 3.79 (t, J=7.2 Hz, 1H) 3.61-3.69 (m, 1H) 3.50 -3.56 (m, 1H) 3.44 (t, J=8.4 Hz, 1H) 2.80 (dd, J=9.6,6.0 Hz, 2H) 2.31-2.39 (m, 2H).

Example 39:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol(Compound 65)

Compound 65 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=642.3. ¹H NMR (400 MHz, CD₃OD) δ8.51 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 7.59 (brd, J=8.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.47 (br s, 1H), 7.32 (s, 1H),5.45 (q, J=5.2 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H),4.38-4.20 (m, 3H), 4.19-4.13 (m, 1H), 4.12-3.99 (m, 2H), 3.91 (t, J=7.6Hz, 1H), 3.85 (br d, J=4.4 Hz, 1H), 3.78 (dd, J=10.4, 2.8 Hz, 1H),3.74-3.55 (m, 4H), 3.25-3.03 (m, 2H).

Example 40:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol(Compound 36)

Compound 36 was synthesized using methods analogous to those describedin Example 24. LCMS (ES+) m/z (M+H)+=582.1. ¹H NMR (400 MHz, CD₃OD) δ8.54 (s, 1H), 7.74 (d, J=8 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.58 (d,J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.46 (s, 1H), 7.32 (br s, 1H),5.45 (q, J=5.2 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.47 (t, J=4.8 Hz, 1H),4.33-4.25 (m, 1H), 4.20 (s, 2H), 4.19-4.13 (m, 1H), 4.11-4.05 (m, 1H),3.91 (dd, J=7.2, 8.0 Hz, 1H), 3.78 (s, 6H), 3.61 (t, J=8.8 Hz, 1H).

Example 41:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol(Compound 66)

Compound 66 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=578.2. ¹H NMR (400 MHz, CD₃OD) δ7.71-7.61 (m, 4H), 7.48 (d, J=8.0 Hz, 2H), 7.46 (s, 1H), 7.40 (d, J=8.0Hz, 2H), 7.31 (s, 1H), 5.45 (q, J=5.2 Hz, 1H), 4.94 (t, J=5.2 Hz, 1H),4.47 (t, J=5.2 Hz, 1H), 4.29-4.27 (m, 1H), 4.20-4.12 (m, 1H), 4.11-4.04(m, 1H), 3.90 (dd, J=6.8, 8.0 Hz, 1H), 3.77-3.67 (m, 6H), 3.60 (t, J=8.6Hz, 1H), 3.20 (s, 4H).

Example 42:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)propane-1,3-diol(Compound 40)

Compound 40 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=522.2. ¹H NMR (400 MHz, CD₃OD) δ7.75 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H),7.52 (d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.32 (br s, 1H), 5.45 (d, J=5.2Hz, 1H), 4.59 (br s, 3H), 4.47 (t, J=4.8 Hz, 1H), 4.30-4.28 (m, 1H),4.21 (s, 2H), 4.19-4.13 (m, 1H), 4.11-4.05 (m, 1H), 3.91 (dd, J=6.8, 8.2Hz, 1H), 3.83-3.78 (m, 2H), 3.77-3.70 (m, 2H), 3.61 (t, J=8.6 Hz, 1H),3.12 (t, J=5.2 Hz, 1H).

Example 43:4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-hydroxyethyl)butanamide(Compound 37)

Compound 37 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=607.2. ¹ NMR (400 MHz, CD₃OD) δ7.81 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H),7.54 (d, J=8.0 Hz, 2H), 7.50 (s, 1H), 7.36 (s, 1H), 5.46 (q, J=5.2 Hz,1H), 4.97 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 4.30-4.26 (m, 3H),4.15-4.13 (m, 2H), 3.90 (dd, J1=8.4 Hz, J2=6.8 Hz, 1H), 3.63-3.60 (m,3H), 3.35-3.31 (m, 2H), 3.15 (t, J=7.2 Hz, 2H), 2.44 (t, J=6.8 Hz, 2H),2.01 (t, J=6.8 Hz, 2H).

Example 44:4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(1,3-dihydroxypropan-2-yl)butanamide(Compound 38)

Compound 38 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=637.2. ¹H NMR (400 MHz, CD₃OD) δ7.81 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H),7.59 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (s, 1H), 5.48 (q, J=5.2 Hz,1H), 5.01 (t, J=5.2 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 4.30-4.26 (m, 3H),4.15-4.13 (m, 2H), 4.02-3.94 (m, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.65-3.58(m, 5H), 3.16 (t, J=7.2 Hz, 2H), 2.47 (t, J=6.8 Hz, 2H), 2.01 (t, J=6.8Hz, 2H).

Example 45:(3R,3aR,6R,6aR)-6-((5-(4′-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 67)

Compound 67 was synthesized using methods analogous to those describedin Example 24. LCMS: (ES+) m/z (M+H)+=547.4. ¹H NMR (400 MHz, DMSO-d₆) δ7.71 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H),7.44 (s, 1H) 7.35 (d, J=8.0 Hz, 2H), 7.30 (s, 1H), 5.42 (q, J=6.0 Hz,1H), 4.82 (t, J=5.2 Hz, 1H), 4.36 (br t, J=4.8 Hz, 1H), 4.07-4.18 (m,3H), 3.87-3.85 (m, 1H), 3.78 (br t, J=7.2 Hz, 1H), 3.56 (s, 2H), 3.43(t, J=8.4 Hz, 1H), 3.22 (br t, J=7.2 Hz, 2H), 2.87 (br t, J=6.0 Hz, 2H),2.61-2.81 (m, 2H), 2.30-2.43 (m, 1H).

Example 46: Synthesis and purification of dimethyl(4′-(6-chloro-2-(((4aR,7S,7aR)-2,2-di-tert-butyltetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonate(Intermediate 46-7A) and dimethyl(4′-(6-chloro-2-(((4aS,7R,7aS)-2,2-di-tert-butyltetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonate(Intermediate 46-7B)

Step 1: A mixture of 4-bromo-4′-iodo-1,1′-biphenyl (3.0 g, 8.4 mmol, 1.0eq) in THF (50 mL) was degassed and purged with N₂ 3 times, and then themixture was cooled to −65° C. n-BuLi (2.5 M, 3.3 mL, 1.0 eq) was added,and the mixture was stirred at −65° C. under N₂ atmosphere. Dimethylphosphorochloridate (1.2 g, 8.4 mmol, 0.90 mL, 1.0 eq) in THF (3 mL) wasadded, and the mixture was stirred at −65° C. for 2 hours under N₂atmosphere. The reaction mixture was quenched by addition of water (20mL) at −50° C., then was added EtOAc (100 mL), and the pH adjusted to 7by addition of aqueous HCl (1M). The reaction mixture was partitioned.The organic phase was separated, washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether: Ethyl acetate=1: 0 to 1: 1) to give 46-1 as the crudeproduct. The crude product was purified by RP-MPLC (column: WelchXtimate C18 100×25 mm×3 um; mobile phase: [A: water (0.025% FA), B:ACN]; B%: 30%-50%) to give 46-1 (0.54 g, 19% yield) as a yellow solid.LCMS: (ES+) m/z (M+H)+=340.9, 342.9. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd,J=8.4, 13.2 Hz, 2H), 7.70 -7.63 (m, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.48(d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.79 (s, 3H).

Step 2: A mixture of 46-1 (0.50 g, 1.5 mmol, 1.0 eq),4,4,4′,4′,5,5,5′,5′-octamethyl −-2,2′-bi(1,3,2-dioxaborolane) (1.1 g,4.4 mmol, 3.0 eq), KOAc (0.72 g, 7.3 mmol, 5.0 eq), andPd(dppf)Cl₂·CH₂Cl₂ (0.12 g, 0.15 mmol, 0.10 eq) in dioxane (20 mL) wasdegassed and purged with N₂ 3 times, and then the mixture was stirred at80° C. for 12 hours under N₂ atmosphere. The reaction mixture wasfiltered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleum ether:Ethyl acetate=20: 1 to 1:3) to give 46-2 (0.50 g, 88% yield) as a yellowsolid. LCMS: (ES+) m/z (M+H)+=389.1. ¹H NMR (400 MHz, CDCl₃) δ 7.95-7.82(m, 4H), 7.72 (dd, J=3.6, 8.4 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 3.80 (s,3H), 3.78 (s, 3H), 1.37 (s, 12H).

Step 3: To a solution of (2R,3S,4S)-pentane-1,2,3,4,5-pentaol (4.0 g, 26mmol, 1.0 eq) and CB_(R4) (—g, 39 mmol, 1.5 eq) in DMF (40 mL) was addedPPh₃ (10 g, 39 mmol, 1.5 eq) in DMF (10 mL) at 0° C. The mixture wasstirred at 18° C. for 1 hour. The reaction mixture was concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether: Ethyl acetate=1: 2 to 0:1, then Ethyl acetate: Methanol=20:1 to 5:1) to give a racemic mixtureof 46-3A and 46-3B (1.6 g, 45% yield) as a colorless oil. ¹H NMR (400MHz, CD₃OD) δ 4.18-4.09 (m, 1H), 4.05-3.93 (m, 2H), 3.80-3.67 (m, 3H),3.60-3.51 (m, 1H).

Step 4: To a solution of a mixture of 46-3A and 46-3B (1.6 g, 12 mmol,1.0 eq) in pyridine (12 g, 0.15 mol, 12 mL, 12 eq) was addeddi-tert-butylsilanediyl bis(trifluoromethanesulfonate) (5.4 g, 12 mmol,1.0 eq) at 0° C. through an injection syringe over a period of 10 mins.The mixture was warmed to 18° C. slowly and stirred at 18° C. for 1hour. The solvent was removed in vacuo, and the residue was partitionedbetween water (35 mL) and DCM (100 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether: Ethyl acetate=100: 1 to 5: 1) togive a mixture of 46-4A and 46-4B (2.3 g, 68% yield) as a white solid.¹H NMR (400 MHz, CD₃CN) δ 4.37-4.31 (m, 1H), 4.25 (br s, 1H), 4.14 (dd,J=4.0, 10.1 Hz, 1H), 3.90-3.76 (m, 3H), 3.72 (d, J=10.0 Hz, 1H), 3.03(s, 1H), 1.96 (td, J=2.4, 4.8 Hz, 2H), 1.07 (s, 9H), 1.04 (s, 9H).

Step 5: To a solution of a mixture of 46-4A and 46-4B (0.30 g, 1.1 mmol,1.1 eq), 6-chloro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (0.50 g, 1.0 mmol, 1.0eq), and 4 Å MS (1.0 g) in DMF (15 mL) was added DBU (0.23 g, 1.5 mmol,0.23 mL, 1.5 eq). The mixture was stirred at 25° C. for 16 hours. Thereaction mixture was filtered, quenched by addition of water (15 mL),and then extracted with DCM (50 mL×2). The combined organic layers werewashed with brine (15 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether: Ethyl acetate=1: 0 to20: 1) to give a racemic mixture of 46-5A and 46-5B (0.31 g, 43% yield)as a white solid. LCMS: (ES+) m/z (M+H)+=682.0. ¹H NMR (400 MHz, CDCl₃)δ 7.78 (s, 1H), 5.73 (t, J=4.4 Hz, 1H), 5.57-5.52 (m, 1H), 5.42 (d,J=11.2 Hz, 1H), 4.53-4.46 (m, 2H), 4.18-4.11 (m, 2H), 4.05 (dt, J=4.4,10.0 Hz, 1H), 3.99-3.85 (m, 2H), 3.73-3.61 (m, 2H), 1.08 (s, 9H), 1.02(s, 9H), 0.97-0.92 (m, 2H), 0.04-0.02 (m, 9H).

Step 6: To a solution of mixture of 46-5A and 46-5B (0.30 g, 0.44 mmol,1.0 eq) and 46-2 (0.25 g, 0.66 mmol, 1.5 eq) in dioxane (10 mL), H₂O (2mL) was added K₃PO₄ (0.47 g, 2.2 mmol, 5.0 eq) and Pd(dppf)Cl₂ (64 mg,88 umol, 0.20 eq) in the glovebox. The mixture was stirred at 90° C. for8 hours. The reaction mixture was filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether: Ethyl acetate=10: 1 to 1: 1) andthen by prep-TLC (SiO₂, Petroleum ether: Ethyl acetate=1: 2) to give amixture of 46-6A and 46-6B (0.18 g, 50% yield) as a yellow oil. LCMS:(ES+) m/z (M+H)+=816.2. ¹H NMR (400 MHz, CDCl₃) δ 7.98-7.88 (m, 5H),7.84-7.78 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 5.80 (t, J=4.4 Hz, 1H), 5.64(d, J=11.2 Hz, 1H), 5.50 (d, J=11.2 Hz, 1H), 4.62-4.47 (m, 2H),4.26-4.17 (m, 2H), 4.16-4.06 (m, 1H), 4.04-3.97 (m, 1H), 3.86 (d, J=11.2Hz, 6H), 3.80-3.68 (m, 2H), 1.12 (s, 9H), 1.07 (s, 9H), 0.99 (dd, J=6.8,9.6 Hz, 2H), 0.00 (s, 9H).

Step 7: The racemic mixture of 46-6A and 46-6B was separated andpurified by prep-HPLC (column: DAICEL CHIRALPAK IG (250 mm×30 mm,10 um);mobile phase: [A: water (0.1% NH₃·H₂O), B: EtOH]; B%: 45%) to give 46-7Aand 46-7B.

46-7A (Peak 1) (100 mg, 45% yield) as a yellow oil. LCMS: (ES⁺) m/z(M+H)⁺=816.2. SFC: tR=1.336 min. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H),7.96-7.85 (m, 5H), 7.80-7.74 (m, 2H), 7.71 (d, J=8.4 Hz, 2H), 5.77 (t,J=4.4 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H), 5.47 (d, J=11.2 Hz, 1H),4.59-4.44 (m, 2H), 4.22-4.12 (m, 2H), 4.07 (dt, J=4.8, 10.0 Hz, 1H),4.00-3.91 (m, 1H), 3.82 (d, J=11.2 Hz, 6H), 3.77-3.66 (m, 2H), 1.08 (s,9H), 1.03 (s, 9H), 0.95 (dd, J=6.8, 9.5 Hz, 2H), —0.04 (s, 9H).46-7B (Peak 2) (90 mg, 41% yield) as a yellow oil. LCMS: (ES⁺) m/z(M+H)⁺=816.2. SFC: tR=1.474 min. ¹H NMR (400 MHz, CDCl₃) δ 7.96-7.84 (m,5H), 7.77 (dd, J=4.0, 8.0 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 5.77 (t,J=4.4 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H), 5.47 (d, J=11.2 Hz,1H),4.57-4.44 (m, 2H), 4.22-4.12 (m, 2H), 4.07 (dt, J=4.8, 9.6 Hz, 1H),3.99-3.92 (m, 1H), 3.82 (d, J=11.2 Hz, 6H), 3.75-3.66 (m, 2H), 1.08 (s,9H), 1.03 (s, 9H), 0.95 (dd, J=6.8, 9.6 Hz, 2H), −0.04 (s, 9H).

Example 47:(4′-(6-chloro-2-(((3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid; (Compound 45)

Step 1: To a solution of 46-7A (Peak 1) (60 mg, 73 umol, 1.0 eq) in DCM(10 mL) was added TMSBr (0.56 g, 3.67 mmol, 0.48 mL, 50 eq) at 0° C. Themixture was stirred at 30° C. for 2 hours. The reaction mixture wasconcentrated under reduced pressure to give the intermediate (50 mg,crude) as a yellow oil, which was used into the next step withoutfurther purification. LCMS: (ES+) m/z (M+H)+=658.3.

Step 2: To a solution of the intermediate obtained in the previous step(50 mg, 76 umol, 1.0 eq) in THF (8 mL) was added pyridine hydrofluoride(45 mg, 0.45 mmol, 41 uL, 6.0 eq) in THF (0.20 mL) at 0° C. under N₂.The mixture was stirred at 0-30° C. for 2 hours. The reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas purified by prep-HPLC (column: Welch Xtimate C18 100×25 mm×3 um;mobile phase: [A: water (0.05% HCl), B: ACN];

B%: 10%-30%) to give Compound 45 (14 mg, 34% yield) as a white solid.LCMS: (ES+) m/z (M+H)+=518.0. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 1H),7.89-7.75 (m, 9H), 5.55-5.49 (m, 1H), 5.33 (t, J=5.2 Hz, 1H), 4.53 (q,J=5.2 Hz, 1H), 4.29 (dd, J=5.2, 6.8 Hz, 1H), 4.21 (dd, J=4.8, 10.4 Hz,1H), 4.10-4.03 (m, 1H), 3.93 (dd, J=3.2, 10.4 Hz, 1H), 3.81-3.75 (m,1H).

Example 48:(4′-(6-chloro-2-(((3R,4S,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid (Compound 68)

Compound 68 was synthesized using 46-7B obtained from Example 46 andusing methods analogous to those described in Example 47. LCMS: (ES+)m/z (M+H)+=518.0. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.97-7.76(m, 9H), 5.63-5.56 (m, 1H), 5.40 (t, J=5.2 Hz, 1H), 4.60 (q, J=5.2 Hz,1H), 4.36 (dd, J=5.2, 6.8 Hz, 1H), 4.28 (dd, J=4.8, 10.4 Hz, 1H), 4.17-4.11 (m, 1H), 4.00 (br dd, J=3.2, 10.4 Hz, 1H).

Example 49:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-sulfonicacid (Compound 69)

Step 1: To a solution of 1-bromo-4-phenyl-benzene (1 g, 4.3 mmol, 1 eq)in CHCl₃(4 mL) was added chlorosulfonic acid (0.63 g, 5.4 mmol, 0.36 mL,1.3 eq). The mixture was stirred at 25° C. for 1 hour .The resultingprecipitate was collected by vacuum filtration, washed with DCM at 0°C., then dried to give 49-1 (0.82 mg, crude) as a black brown solid.LCMS: (ES-) m/z (M-1)-=313.0.

Step 2: A mixture of 49-1 (0.49 g, 1.6 mmol, 1 eq) in SOCl₂ (4.9 mL) wasstirred at 80 ° C. for 2 hours. The reaction mixture was concentratedunder reduced pressure to give 49-2 (0.49 mg, crude) as a black brownsolid.

Step 3: To a solution of 49-2 (0.49 g, 1.5 mmol, 1 eq) in DCM (5 mL) wasadded TEA (0.30 g, 3.0 mmol, 0.41 mL, 2 eq) and1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (0.46 g, 1.8mmol, 1.2 eq). The mixture was stirred at 25° C. for 12 hours. Thereaction was quenched by addition of H₂O (3 mL) and then extracted withEA (9 mL×3). The combined organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated under pressure to give 49-3 (0.83 g, crude) asa black brown oil. LCMS: (ES+) m/z (M+H)+=574.2.

Step 4: To a solution of 49-3 (0.83 mg, 1.5 mmol, 1 eq) in dioxane (8.3mL) was added Pd(dppf)Cl₂·CH₂Cl₂ (0.12 g, 0.15 mmol, 0.1 eq), BPD (0.57g, 2.3 mmol, 1.5 eq) and KOAc (0.37 g, 3.8 mmol, 2.5 eq). The mixturewas stirred at 80° C. for 2 hours. The reaction was quenched by additionof H₂O (10 mL) and then extracted with EA (30 mL×3). The combinedorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedunder pressure to give 49-4 (1.9 g, crude) as a black brown solid. LCMS:(ES+) m/z (M+H)+=622.4.

Step 5: To a solution of 49-4 (2 g, 3.4 mmol, 2 eq) in dioxane (20 mL)was added2-[[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-6-chloro-5-iodo-imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane(1.1 g, 1.7 mmol, 1 eq), K₂CO₃ (0.46 g, 3.3 mmol, 2 eq) andPd(dppf)Cl₂·CH₂Cl₂ (0.14 g, 0.17 mmol, 0.1 eq). The mixture was stirredat 80° C. for 2 hours. The reaction was quenched by addition of H₂O (30mL) and then extracted with EA (30 mL×3). The combined organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated under pressure.The residue was purified by flash silica gel chromatography (ISCO®; 25 gSepaFlash® Silica Flash Column, Eluent of 0-70% Ethyl acetate/Petroleumether gradient) to give 49-5 (1.8 g, 72% yield) as a yellow solid. LCMS:(ES+) m/z (M+H)+=1013.6.

Step 6: A mixture of 49-5 (1.7 g, 1.7 mmol, 1 eq) in TFA (18 mL) wasstirred at 25° C. for 12 hours. The reaction mixture was concentratedunder reduced pressure to give 49-6 (1.3 g, crude) as a black brownsolid. LCMS: (ES+) m/z (M+H)+=529.2.

Step 7: To a solution of 49-6 (0.40 g, 0.76 mmol, 1 eq) in conc. HCl(12M in H₂O, 3.3 mL)/THF (3.5 mL) was added NaNO₂ (0.13 g, 1.9 mmol, 2.5eq). The mixture was stirred at 40° C. for 2 hours. The reaction wasquenched by addition of saturated aqueous Na₂CO₃ solution and thenextracted with THF (10 mL×3). The combined organic phase was washed withH₂O (10 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder pressure. The mixture was further purification by prep-HPLC(column: Welch Xtimate C18 150×25 mm×5 um; mobile phase: [A: water(0.05% HCl), B: ACN]; B%: 12%-42%) and then lyophilized to give Compound69 (7.9 mg, —umol, 1% yield, HCl) as a white solid. LCMS: (ES+) m/z(M+H)+=530.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.96 (s, 1H), 7.81-7.72(m, 4H), 7.71 (s, 4H), 5.49 (q, J=5.6 Hz, 1H), 4.84 (t, J=5.2 Hz, 1H),4.37 (br s, 1H), 4.16 (br s, 1H), 4.09 (br s, 1H), 3.95-3.91 (m, 1H),3.79 (t, J=7.2 Hz, 1H), 3.44 (t, J=8.4 Hz, 1H).

Example 50:4′-(6-chloro-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-sulfonamide(Compound 70)

Step 1: A mixture of 4′-bromo-[1,1′-biphenyl]-4-sulfonic acid (2.0 g,6.4 mmol, 1 eq) in SOCl₂ (20 mL) was stirred at 80° C. for 2 hours. Thereaction mixture was concentrated in vacuo to give 50-1 (2.0 g, crude)as a brown solid.

Step 2: A mixture of 50-1 (2.0 g, 6.0 mmol, 1 eq),2-(2-aminoethoxy)ethanol (0.71 g, 6.6 mmol, 0.67 mL, 1.1 eq), and TEA(1.8 g, 18 mmol, 2.5 mL, 3 eq) in DCM (20 mL) was stirred at 25° C. for2 hours. The mixture was poured into water (20 mL) and then extractedwith ethyl acetate (20 mL×2). The combine organic layers were washedwith saturated brine (20 mL×2) and concentrated in vacuo to give 50-2(2.4 g, crude) as a brown solid. LCMS: (ES+) m/z (M+H)+=400.2.

Step 3: A mixture of 50-2 (2.3 g, 5.8 mmol, 1 eq), BPD (2.2 g, 8.6 mmol,1.5 eq), Pd(dppf)Cl_(2.)CH₂Cl₂ (0.71 g, 0.87 mmol, 0.15 eq) and KOAc(1.7 g, 17 mmol, 3 eq) in dioxane (25 mL) was degassed and purged withN2 3 times, and then the mixture was stirred at 80° C. for 3 hours underN₂ atmosphere. The mixture was poured into water (30 mL), then extractedwith ethyl acetate (2×30 mL). The combine organic layers were washedwith saturated brine (2×30 mL) and concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50:1 to 1:1) to afford 50-3 (2.1 g, 81% yield) as a brown solid.LCMS: (ES+) m/z (M+H)+=448.2.

Step 4: A mixture of 50-3 (1.5 g, 3.4 mmol, 1 eq) , 50-4 (2.7 g, 4.0mmol, 1.2 eq; synthesized by procedures analogous to those described inExample 1), Pd(dppf)Cl₂ (0.55 g, 0.75 mmol, 0.1 eq), KOAc (1.0 g, 10mmol, 3 eq) and H₂O (4 mL) in dioxane (20 mL) was degassed and purgedwith N₂ 3 times. The mixture was stirred at 90° C. for 3 hours under N₂atmosphere. The mixture was poured into water (30 mL), then extractedwith ethyl acetate (2×30 mL). The combine organic layers were washedwith saturated brine (2×30 mL) and concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50:1 to 0:1) to afford 50-5 (2.1 g, 81% yield) as a brown solid.LCMS: (ES+) m/z (M+H)+=448.2.

Step 5: A solution of 50-5 (0.5 g, 0.59 mmol, 1 eq) and TFA (3.8 g, 34mmol, 2.5 mL, 58 eq) in DCM (5 mL) was stirred at 25° C. for 12 hours.The mixture was concentrated in vacuo to give 50-6 (0.75 g, crude) as ablack solid. LCMS: (ES+) m/z (M+H)+=712.1.

Step 6: A solution of 50-6 (0.42 g, 0.51 mmol, 1 eq, TFA salt), LiOH·H2O(64 mg, 1.5 mmol, 3 eq) and H₂O (1.6 mL) in EtOH (8 mL) was stirred at25° C. for 6 hours. The reaction mixture was concentrated in vacuo. Theresidue was purified by Prep-HPLC (column: Phenomenex luna C18 150×25mm×10 um; mobile phase: [A: water (0.225% FA), B: ACN]; B%: 27%-57%) toafford Compound 70 (68 mg, 21% yield) as a yellow solid. LCMS: (ES+) m/z(M+H)+=616.2. ¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (s, 1H), 7.98 (d, J=8.0Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H), 7.75 (s, 1H),7.58 (d, J=8.0 Hz, 2H), 7.55-7.22 (m, 2H), 5.54-5.38 (m, 1H), 4.98 (d,J=6.8 Hz, 1H), 4.83 (t, J=4.8 Hz, 1H), 4.55 (t, J=5.2 Hz, 1H), 4.37 (t,J=4.8 Hz, 1H), 4.23-4.09 (m, 2H), 3.95-3.85 (m, 1H), 3.95-3.85 (m, 1H),3.84-3.74 (m, 1H), 3.48-3.35 (m, 7H),2.89-3.03 (q, J=5.2 Hz, 2H).

Example 51:4′-(6-chloro-2—O(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide(Compound 71)

Compound 71 was synthesized using methods analogous to those describedin Example 50. LCMS: (ES+) m/z (M)+=692.2. ¹H NMR (400 MHz, DMSO-d₆) δ12.39-12.17 (m, 1H) 7.98-7.93 (m, 2H) 7.92-7.87 (m, 2H) 7.83 (d, J=8.0Hz, 2H) 7.57 (br d, J=8.0 Hz, 2H) 7.52 (br d, J=5.2 Hz, 1H) 5.48-5.38(m, 1H) 4.97 (d, J=6.8 Hz, 1H) 4.86-4.73 (m, 2H) 4.47 (d, J=5.6 Hz, 1H)4.39-4.26 (m, 4H) 4.19-4.09 (m, 2H) 3.94-3.84 (m, 1H) 3.79 (t, J=7.2Hz,1H) 3.69-3.59 (m, 3H) 3.58-3.52 (m, 1H) 3.44 (br t, J=8.4 Hz, 3H) 3.37(br dd, J=10, 5.2 Hz, 4H).

Example 52: 4′-(6-chloro-2-0(3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-sulfonamide(Compound 72)

Compound 77 was synthesized using methods analogous to those describedin Example 50. LCMS: (ES+) m/z (M+H)+=630.1. ¹ NMR (400 MHz, DMSO-d₆) δ12.30 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.92-7.79 (q, 4H), 7.60 (d, J=8.4Hz, 2H), 7.40 (s, 1H), 7.15 (s, 1H), 5.45 (s, 1H), 5.00 (d, J=6.8 Hz,1H), 4.80 (t, J=4.8 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 4.37 (t, J=4.8 Hz,1H), 4.26-4.06 (m, 2H), 3.95-3.74 (m, 2H), 3.57 (t, J=5.6 Hz, 2H),3.50-3.44 (m, 3H), 3.43-3.38 (m, 2H), 3.22 (t, J=4.2 Hz, 2H), 2.80 (s,3H).

Example 53: (2R,3R,4R,5S)-6-(1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-13]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)ethyl)amino)hexane-1,2,3,4,5-pentaol(Compound 73)

Step 1: A mixture of2-[[2-[[(3R,3aR,6R,6aS)-6-[tert-butyl(dimethyl)silyl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]-6-chloro-5-iodo-imidazo[4,5-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (1.5 g, 2.25 mmol, 1eq) and4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,2-dioxaborolane(889 mg, 2.69 mmol, 1.2 eq) in DMSO (15 mL) was degassed and purged withN₂ ₃ times. Then to the mixture was added Na₂CO₃ (661 mg, 6.24 mmol, 2.8eq) and Pd(dppf)Cl₂.CH₂Cl₂ (183 mg, 225 umol, 0.1 eq). The mixture wasstirred at 80° C. for 16 hours under N₂ atmosphere. The reaction mixturewas quenched by addition of H₂O (50 mL) and extracted with EA (50 mL×3).The combined organic layers were washed with saturated aqueous NaCl (50mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=4/1 to 3/1) to give53-1 (730 mg, 44% yield) as a brown oil. LCMS: (ES+) m/z (M)+=744.2.

Step 2: To a solution of 53-1 (400 mg, 537 umol, 1 eq) and1-(4-bromophenyl) ethanone (128 mg, 645 umol, 1.2 eq) in dioxane (4 mL)and H₂O (1.0 mL) was added K2CO₃ (371 mg, 2.69 mmol, 5 eq) andPd(dppf)Cl₂.CH₂Cl₂ (88 mg, 107 umol, 0.2 q). The mixture was stirred at80° C. for 2 hours. The reaction mixture was quenched by addition of H₂O(30 mL) and extracted with EA (20 mL×3). The combined organic layerswere washed with saturated aqueous NaC1 (20 mL×2), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=5/1 to 4/1) to give 53-2 (232 mg, 59% yield) as abrown oil. LCMS: (ES+) m/z (M)+=736.3.

Step 3: A solution of 53-2 (230 mg, 312 umol, 1 eq) in HC1/dioxane (4 M,1.95 mL, 25 eq) was stirred at 25° C. for 2 hours. The reaction mixturewas quenched by addition of H₂O (20 mL), and then the pH was adjusted to7 with saturated aqueous Na₂CO₃ solution. The combined organic layerswere washed with EA (20 mL×3), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give 53-3 (113 mg, crude) asyellow solid, which was used into the next step without furtherpurification.

Step 4: To a solution of 53-3 (190 mg, 386 umol, 1 eq) and(2R,3R,4R,5S)-6-aminohexane-1,2,3,4,5-pentaol (280 mg, 1.54 mmol, 4 eq)in THF (5 mL) and DMSO (5 mL) was added AcOH (70 mg, 1.16 mmol, 66 uL, 3eq) and NaBH(OAc)₃ (164 mg, 772 umol, 2 eq). The mixture was stirred at25-40° C. for 48 hours. The reaction solution was concentrated underreduced pressure to remove THF and filtered, and then the mixture waspurified by prep-HPLC (column: Phenomenex Synergi Polar-RP 100×25 mm×4um; mobile phase: [A: water (0.225% FA), B: ACN]; B%: 10%-40%) to giveCompound 73 (35.37 mg, 58% yield) as a white solid. LCMS: (ES+) m/z(M)+=657.1. ¹H NMR (400 MHz, CD₃OD) δ 8.53 (s, 1H), 7.85-7.71 (m, 7H),7.57 (d, J=8.2 Hz, 2H), 5.55 (q, J=5.2 Hz, 1H), 4.97 (t, J=5.2 Hz, 1H),4.47 (t, J=4.8 Hz, 1H), 4.39-4.24 (m, 2H), 4.21-4.14 (m, 1H), 4.14-4.08(m, 1H), 4.06-3.95 (m, 1H), 3.93-3.86 (m, 1H), 3.84-3.73 (m, 2H),3.70-3.57 (m, 4H), 3.09-3.02 (m, 1H), 3.00-2.86 (m, 1H), 1.67 (d, J=6.8Hz, 3H).

Example 54:(3R,3aR,6R,6aR)-6-(6-chloro-5-(2′-hydroxy-4′-((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzoldlimidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol(Compound 74)

Compound 74 was synthesized using methods analogous to those describedin Example 53. LCMS: (ES+) m/z (M)+=582.4. ¹H NMR (400 MHz, CD₃OD) δ8.53-8.38 (m, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.53-7.38 (m, 4H), 7.36-7.26(m, 1H), 7.10-7.00 (m, 2H), 5.45 (q, J=5.2 Hz, 1H), 4.94 (t, J=5.2 Hz,1H), 4.47 (t, J=5.2 Hz, 1H), 4.33-4.25 (m, 1H), 4.22-4. —(m, 3H), 4.11-4.04 (m, 1H), 3.91 (dd, J=8.4, 6.8 Hz, 1H), 3.81-3.70 (m, 4H),3.65-3.57 (m, 3H), 3.29-3.25 (m, 2H).

Example 55:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide(Compound 75)

Step 1: To a solution of methyl 4-bromo-3-hydroxybenzoate (2.5 g, 11mmol, 1 eq) in DMF (30 mL) was added K2CO₃ (3.1 g, 23 mmol, 2.1 eq).Then chloro(methoxy)methane (1.3 g, 16 mmol, 1.2 mL, 1.5 eq) was addeddropwise at 0° C. The mixture was stirred at 25° C. for 2 hours. Thereaction was quenched by addition of H₂O (15 mL) and then extracted withEA (15 mL×3). The combined organic phase was washed with saturated brine(15 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated underpressure. The residue was purified by flash silica gel chromatography(ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethylacetate/Petroleum ether gradient) to give 55-1 (1.6 g, 54% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77 (d, J=2.0 Hz, 1H),7.59-7.65 (m, 1H), 7.55 (dd, J=8.0, 2.0 Hz, 1H), 5.30 (s, 2H), 3.90 (s,3H), 3.53 (s, 3H).

Step 2: To a solution of 55-1 (1.2 g, 1.6 mmol, 1 eq) and2-(((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyl)oxy)hexahydrofuro[3,2-b]furan-3-yl)oxy)-6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(prepared with procedures analogous to Example 53 for compound 53-1)(0.53 g, 1.9 mmol, 1.2 eq) in dioxane (12 mL) was added Pd(PPh₃)₄ (0.28g, 0.24 mmol, 0.15 eq) and K₂CO₃ (0.67 mg, 4.8 mmol, 3 eq). The mixturewas stirred at 100° C. for 2 hours. The reaction was quenched byaddition of H₂O (10 mL) and then extracted with DCM (12 mL×3). Thecombined organic phase was washed with saturated brine (10 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated under pressure. Theresidue was purified by flash silica gel chromatography (ISCO®; 24 gSepaFlash® Silica Flash Column, Eluent of 0-45% Ethyl acetate/Petroleumethergradient) to give 55-2 (0.47 g, 23% yield) as a colorless oil.LCMS: (ES+) m/z (M+H)+=811.6.

Step 3: To a solution of 55-2 (0.47 g, 0.58 mmol, 1 eq) in THF (4.7mL)/H₂O (0.94 mL) was added LiOH·H2O (49 mg, 1.16 mmol, 2 eq). Themixture was stirred at 25° C. for 2 hours. The reaction was adjusted topH 6 with 1M aqueous HCl solution, then extracted with EA (7 mL×3). Thecombined organic phase was washed with saturated brine (7 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated under pressure. Thecrude product (50 mg) was further purification by pre-HPLC (column:Phenomenex luna C18 150×25 mm×10 um; mobile phase: [A: water (0.225%FA), B: ACN]; B%: 80%-100%) to give 55-3 (0.48 g, 59% yield) as acolorless oil. LCMS: (ES+) m/z (M+H)+=797.6.

Step 4: To a solution of 55-3 (0.48 g, 0.59 mmol, 1 eq) in DMF (4 mL)was added HATU (0.34 g, 0.9 mmol, 1.5 eq), 2-(2-aminoethoxy)ethanol (75mg, 0.72 mmol, 71 uL, 1.2 eq) and DIPEA (0.23 g, 1.8 mmol, 0.31 mL, 3eq). The mixture was stirred at 25° C. for 2 hours. The reaction wasquenched by addition of H₂O and then extracted with EA (8 mL×3). Thecombined organic phase was washed with saturated brine (8 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated under pressure to give55-4 (0.46 g, crude) as a yellow oil. LCMS: (ES+) m/z (M+H)+=884.5.

Step 5: A mixture of 55-4 (0.45 mg, 0.51 mmol, 1 eq) in DCM (0.5 mL)/TFA(0.1 mL) was stirred at 25° C. for 12 hours. The reaction mixture wasdirectly concentrated under reduced pressure to give 55-5 (0.55 g,crude) as a red oil. LCMS: (ES+) m/z (M+H)+=692.2.

Step 6: To a solution of 55-5 (0.55 g, 0.80 mmol, 1 eq) in EtOH (5mL)/H₂O (1 mL) was added LiOH·H2O (0.10 g, 2.4 mmol, 3 eq). The mixturewas stirred at 25° C. for 2 hours. The reaction mixture was directlyconcentrated under reduced pressure. The mixture was furtherpurification by prep-HPLC (column: Phenomenex luna C18 150×25 mm×10 um;mobile phase: [A: water (0.225% FA), B: ACN]; B%: 20%-50%) to giveCompound 75 (76 mg, 15% yield) as a white solid. LCMS: (ES+) m/z(M+H)+=596.2. ¹⁻E1 NMR (400 MHz, DMSO-d₆) δ 12.26 (br s, 1H), 9.91 (s,1H), 8.43 (t, J=5.6 Hz, 1H), 7.74-7.33 (m, 9H), 5.49-5.41 (m, 1H), 4.97(br d, J=6.4 Hz, 1H), 4.83 (t, J=5.2 Hz, 1H), 4.61 (br t, J=5.2 Hz, 1H),4.41-4.33 (m, 1H), 4.18-4.08 (m, 2H), 3.88 (dd, J=9.2, 6.4 Hz, 1H),3.83-3.75 (m, 1H), 3.57-3.43 (m, 4H), 3.48-3.41 (m, 5H).

II. Biological Evaluation Example A-1: In Vitro pAMPK1 Kinase ActivationAssay

Compound effect on AMPK enzyme activation was determined in a cell-freeformat with a 12-point concentration curve. The ADP-Glo detection systemwas used to determine phosphorylation of a SAMS peptide substrate.Recombinant AMPK α1/β1/γ1 complex was pre-activated by phosphorylationwith CAMKK2 followed by incubated with compound for 15 minutes prior tothe SAMS phosphorylation reaction. Activity curves and EC₅₀ values werefitted by interpolation to an ATP:ADP standard curve as indicated by theADP-Glo manufacturer using Prism software.

Results for exemplary compounds are shown in Table A.

TABLE A Compound EC₅₀ (nM)^(a) 1 0.05 2 1.4 3 0.09 4 0.1 5 0.86 6 0.62 71.22 8 1.78 9 1.61 10 0.40 11 0.46 12 152 14 0.50 22 0.63 29 0.56 300.65 31 0.85 32 0.76 33 0.96 36 0.84 37 3.6 38 2.4 40 1.08 45 >10000 481.16 49 1.76 50 1.46 51 0.72 52 0.81 53 0.23 54 0.57 55 2.22 56 0.93 570.89 58 0.93 59 1.04 60 0.85 61 1.36 62 1.30 63 1.09 64 1.40 65 0.77 660.80 67 0.93 68 >10000 69 1.84 70 1.51 71 0.63 72 1.38 73 1.33 74 0.1575 0.37 MK-8722 10.4 60 0.85

The compounds of the present invention are one to two orders ofmagnitude more active than the clinically investigated systemic AMPKactivator, MK-8722 (Science 2017, 357 (6350):507-511).

Example A-2: Pharmacokinetic Assays

Oral Bioavailability

Selected compounds were tested for pharmacokinetics in C57BL/6 mice.Compounds 1, 4, 31, 32, 40, 55, 57 and 60 were dosed IV at 1 mg/kg as aformulation of 0.2 mg/mL in 5% DMSO+30% PEG400+65% water and were dosedPO at 30 mg/kg as a formulation of 3 mg/mL in 0.25% MC+5% Tween 80+0.02%SDS. Compound 2 was dosed IV at 1 mg/kg as a formulation of 0.2 mg/mL in5% ethanol +95% saline and was dosed PO at 30 mg/kg as a formulation of3 mg/mL in 0.25% MC+5% Tween 80+0.02% SDS.

Compounds 1, 2, 4, and 32 were shown to have oral bioavailability ofless than 1%; Compounds 31, 40, and 57 were shown to have oralbioavailability of less than 10%; and Compounds 55 and 60 were shown tohave oral bioavailability of less than 15%.

Following IV administration, Compounds 4 and 32 have a volume ofdistribution<1 L/kg, and Compounds 1, 2, 31, 40, 55, 57, and 60 have avolume of distribution of <5 L/kg. Additionally, the half-life forCompound 4 was shown to be 1.4 h and for Compound 31 was shown to be 1.7h. Half-lives for the other compounds tested were between 2 and 6 hours.This indicates that a smaller portion of the absorbed dose makes it intotissues and that any absorbed dose is eliminated rather quickly for thecompounds of the present invention, such as Compound 4, which in turnhave a greatly reduced risk of causing systemic AMPK activation comparedto the systemic AMPK activator MK-8722, which has an oralbioavailability of 82% (Science 2017, 357 (6350):507-511).

Example A-3: Permeability Assessment in the Caco-2 Cell Monolayer

Caco-2 cells purchased from ATCC were seeded onto polyethylene membranes(PET) in 96-well BD Insert plates at 1×10⁵ cells/cm², and refreshedmedium every 4-5 days until to the 21^(st) to 28^(th) day for confluentcell monolayer formation. The transport buffer in the study was HBSSwith 10 mM HEPES at pH 7.40±0.05. Test compounds were tested at 2 μMbi-directionally in duplicate. Digoxin was tested at 10 μMbi-directionally in duplicate, while nadolol and metoprolol were testedat 2 μM in A to B direction in duplicate. Final DMSO concentration wasadjusted to less than 1%.

The plate was incubated for 2 hours in CO₂ incubator at 37±1° C., with5% CO₂ at saturated humidity without shaking. All samples were mixedwith acetonitrile containing internal standard and were centrifuged at4000 rpm for 10 min. Subsequently, 100 μL supernatant solution wasdiluted with 100 μL distilled water for LC/MS/MS analysis.Concentrations of test and control compounds in starting solution, donorsolution, and receiver solution were quantified by LC/MS/MS, using peakarea ratio of analyte/internal standard.

Results for exemplary compounds are shown in Table B.

TABLE B Mean P_(app) (10^(−6 cm/s)) Efflux Mean Recovery (%) Compound Ato B B t oA Ratio A to B B to A Nadolol 0.08 ND — 97.74 ND (control: lowpermeability) Metoprolol 16.37 ND — 90.00 ND (control: highpermeability) Digoxin <0.03 12.70 >437.79 <90.79 92.23 (Pgp substrate)Compound 1 <0.25 0.73 >2.90 <82.61 89.90 Compound 4 <0.480 0.710 >1.48<99.6 102.1 Compound 31 0.115 31.7 275 83.2 97.8

Compounds 1 and 31 were shown to have a large BA/AB efflux ratio (>2).These data indicate that the compounds have low permeability and arelikely a substrates of intestinal efflux transporters. Compound 4 wasshown to have low permeability.

Example A-4: In vitro MDCK Epithelial Permeability Assay

In order to quantitatively measure the effects of transporter substrateAMPK activators on epithelial permeability in vitro, standard calciumswitch protocols from the literature were adapted for use withMadin-Darby Canine Kidney (MDCK) cells grown on Corning Transwellinserts for use with fluorescein isothiocyanate-dextran, averagemolecular weight 4 kDa (FITC-dextran). FITC-dextran is a large,metabolically inert sugar molecule that is not readily transferrableacross healthy epithelial barriers in vitro or in vivo. This compoundhas been tagged with a fluorophore to easily track its movement.

Briefly, MDCK cells were seeded onto Transwell inserts and grownaccording to manufacturer instructions until confluent. On the day ofthe experiment, a baseline reading was taken in standard growth media inwhich FITC-dextran was spiked into the apical chamber and the percentpermeation of FITC-dextran from the apical to the basolateral chamberwas measured. The inserts were then washed in low calcium medium (LCM)containing either vehicle or compound to remove residual FITC-dextranand calcium, and FITC-dextran was once again spiked into the apicalchamber and the percent permeation in LCM was measured. Values weredetermined by reading fluorescence intensity on a standard plate readerand calculated by fitting back to 12-point standard curve in eithergrowth media or LCM+vehicle, respectively. The fold induction ofFITC-dextran permeation to the basolateral chamber when each well wastransferred from baseline growth media to LCM was then calculated.

Compound 1 reduced the amount of FITC-dextran that permeated from theapical chamber to the basolateral chamber in the LCM condition relativeto baseline and showed a reduction of 35% and 33%, respectively, at 10μM and 0.1 μM relative to the vehicle treated epithelial cellmonolayers.

Example A-5: Effects of AMPK Activators on Intestinal .Barrier Functionin a Mouse in vivo Acute Dextran Sulfate Sodium (DSS) Colitis Model

Compounds were formulated in vehicle (0.25% methyl cellulose, 5% Tween80, 0.02% sodium dodecyl sulfate (SDS) in Hanks' Buffered Salt Solutionwith Ca²⁺ and Mg²⁺). Vehicle or compound was administered once daily byoral gavage to C57B1/6 mice. After 3 days of pre-dosing, dextran sulfatesodium (DSS) was simultaneously administered at 3% in drinking water,and appropriate water-only controls were included.

After 7 days of DSS administration, animals treated were switched backto their regular water source and administered a single oral bolus doseof FITC-dextran (FD) four hours prior to necropsy. The animals weresacrificed by cardiac puncture and serum was collected. Theconcentration of HTC-dextran present in serum was determined bymeasuring fluorescence intensity on a standard plate reader, and fittingvalues back to a standard curve.

As shown in Table C, administration of Compound 4 and Compound 31produced reductions in plasma or serum fluorescence intensity comparedto vehicle treatment in animals given DSS. This is indicative ofimproved intestinal barrier function in these compound-treated animalsrelative to vehicle-treated controls..

TABLE C Change in Fluorescence Compound (dose) Intensity vs. Vehicle  4(30 mg/kg QD) −43% 31 (30 mg/kg QD) −41%

Example A-6: Effects of AMPK Activators on Diarrhea in a Mouse in vivoChemotherapy-induced Intestinal Injury Model

Compounds were formulated in vehicle (0.25% methyl cellulose, 5% Tween80, 0.02% sodium dodecyl sulfate (SDS) in Hanks' Buffered Salt Solutionwith Ca' and Mg'). On day 1, either saline or a 400 mg/kg dose of5-fluorouracil (5FU) in saline was administered by intraperitonealinjection to BALB/c mice. Starting on day 2, vehicle or compound wasadministered twice a day by oral gavage. From days 5 to 6 post-5FU, theanimals were scored for diarrhea severity once a day. The diarrhea wasscored 0-3 as follows: 0—normal consistency (black and solid), 1—soft(black and a bit lighter/yellow), 2—loosely shaped stool (yellowish andsomewhat watery), 3—extreme diarrhea (very watery). Day 5 and day 6diarrhea scores following administration of the tested compounds werelower than vehicle control mice suggesting robust protection from5—FU-induced intestinal injury.

Results for exemplary compounds are shown in Table D.

TABLE D Diarrhea Score (% Change vs. Vehicle) Compound (dose) Day 5 Day6  4 (10 mpk BID) 0.25 (−72%) 0.38 (−79%)  4 (3 mpk BID) 0.75 (−16%)1.00 (−44%) 31 (30 mpk BID) 0.43 (−67%) 0.63 (−61%) 32 (20 mpk BID) 0.63(−43%) 0.88 (−52%) 40 (30 mpk BID) 0.38 (−66%) 0.75 (−59%) 56 (30 mpkBID) 0.38 (−71%) 0.25 (−77%) 58 (30 mpk BID) 0.25 (−81%) 0.38 (−66%) 60(30 mpk BID) 0.38 (−71%) 0.38 (−66%)

Example A-7: Effects of AMPK Activators on an Intraperitoneal (IP)Glucose Tolerance Test in Mice

Systemic AMPK target engagement in vivo can be assessed by measuring theglucose levels in blood following administration of compounds, wherebyAMPK activation in skeletal muscle leads in a decrease in overall bloodglucose levels.

Compounds were formulated in vehicle (0.25% methyl cellulose, 5% Tween80, 0.02% sodium dodecyl sulfate (SDS) in Hanks' Buffered Salt Solutionwith Ca²⁺ and Mg²). Immediately prior to compound dosing, the tip of thetail was removed with scissors and a drop of blood was collected onto aglucometer strip (Bayer Contour Next) for a −1 hour blood glucosemeasure. The mice were then immediately administered vehicle or compoundat 10 mL/kg PO. Approximately one hour later, mice were tail bled for a0 min blood glucose reading, and then immediately after wereadministered D(+) glucose (2 g/kg, made up in saline) at 5 mL/kg IP.Tail bleeds were then performed on all mice at 20 min, 40 min, 60 min,and 90 min post D(+) glucose administration for blood glucose measures.Area under the curves (AUCs) for blood glucose measures were thencalculated for each treatment from 0-90 mins. Only the systemic AMPKactivator MK-8722 caused a significant change in the AUC vs. vehiclesuggesting that Compounds 1, 2, and 4 at the administered doses (30 mpkfor all compounds; and up to 100 mpk for Compound 4) do not lead toactivation of AMPK in skeletal muscle.

Results for exemplary compounds are shown in Table E.

TABLE E % Change in Average Total Compound (dose) AUC (0-90 min) vs.Vehicle MK-8722 (30 mpk) −28% 1 (30 mpk) −7.5%  2 (30 mpk) +6.6%  4 (30mpk) −0.9%  4 (100 mpk) +2.3% 

What is claimed is:
 1. A compound of Formula (III):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein: X is —O—or —S—; Y is N or CH; G is monocyclic 3- to6-membered heterocycloalkyl containing 1 oxygen atom, which issubstituted with 1 or 2 substituents selected from —C(O)OH, —CH₂C(O)OH,—P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; or G is bicyclic 8-to 10-membered heterocycloalkyl containing 2 oxygen atoms, which issubstituted with 1 or 2 substituents selected from —C(O)OH, —CH₂C(O)OH,—P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH; D is K or —Z—NR⁵R⁶;Z is —(CH₂)—, —(CH(CH₃)—, —C(═O)—, or —S(═O)₂—; K is —SO—₂OH, —S(O)OH,—P(O)(OH)(R^(d)), —P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)),—B(OR^(d))(OH), —NHC(O)H, —N(R^(d))C(O)NHSO₂(R^(d)), —C(O)NHSO₂(R^(d)),—SO₂NHC(O)(R^(d)), —NHC(O)NH(R^(d)), —N(R^(d))C(═N(R^(d)))N(R^(d))₂,—N(R^(d))C(═NH)NHC(═NH)NH₂,

R^(a) and R^(b) are each independently halogen, —CN, —OH, —OR¹³,—NR¹⁴R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁴,C₁-C₆ alkyl, or C₁-C₆ fluoroalkyl;each R^(d) is independently hydrogen or C₁-₆ alkyl; each R^(e) isindependently C¹⁻⁶ alkyl; each R² is independently halogen, —CN, C₁-C₄alkyl, C₁-C₄ fluoroalkyl, or C₃-C₆ cycloalkyl; R⁵ is C₆-C₁₀ alkyl thatis substituted by 5 to 9 —OH groups; or R⁵ is C₁₋₁₀ alkyl which issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6groups selected from —CO₂H, —OH, and —N(R^(d))₂; and is optionallyfurther substituted by 1, 2, or 3 R^(f) groups; each R^(f) isindependently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴,—C(O)NR¹⁴R¹⁴, NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁴, C₁-C₆ alkyl, C₃-C₆cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, isunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups; or R⁵is —[(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—, or—C(O)N(R^(d))—; or R⁵ is —(C₁-C₆ alkylene)-aryl, or —(C₁-C₆alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by1-6 groups selected from —CO₂H, —OH, —N(R^(d))₂, —N(R^(e))₃ ⁺, and K;and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3R^(f) groups; R⁶ is hydrogen or C₁₋₆ alkyl; or R⁵ and R⁶ are takentogether with the nitrogen to which they are attached to form a 3- to6-membered N-heterocycloalkyl which is substituted with 1-6 groupsselected from —CH₃, —CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH,—N(R^(e))₃ ⁺, and K; or with 2-6 groups selected from —CO₂H, —OH,—CH₂OH, —CH₂NH₂, —CH₂CH₂OH, —CH₂OCH₂CH₂OH, and —N(R^(d))₂; R⁹ ishydrogen, C₁₋₈ alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, ornaphthyl is unsubstituted or substituted by 1-6 groups selected from—OH, —CO₂H, —N(R^(e))₂, —N(R^(e))₃ ⁺, and K; each R¹³ is independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclicheteroaryl; each R¹⁴ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ fluoroalkyl, C₃-C₆ cycloalkyl, 3- to6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or twoR¹⁴ on the same nitrogen atom are taken together with the nitrogen towhich they are attached to form a 3- to 6-membered N-heterocycloalkyl; pis 0 or 1; q is 0 or 1; each s is independently 1-6; and each t isindependently 1-6.
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R²is —F, —Cl, or —CN; R³ is —F, —Cl, —CN, —OH, —OCH₃, —OCF₃, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl,—CH₂F, —CHF2, or —CF₃; and R^(b) is —F, —Cl, —CN, —OH, —OCH₃, —OCF₃,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl,tert-butyl, —CH₂F, —CHF2, or —CF₃.
 3. The compound of claim 1, havingthe structure of Formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.
 4. The compound of claim 1, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof, wherein: X is —O—. 5.The compound of claim 1, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, wherein: G is monocyclic 3- to6-membered heterocycloalkyl containing 1 oxygen atom, which issubstituted with 1 or 2 substituents selected from —C(O)OH, —CH₂C(O)OH,—P(O)(Me)OH, —P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH.
 6. The compound ofclaim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer,or prodrug thereof, wherein: G is bicyclic 8- to 10-memberedheterocycloalkyl containing 2 oxygen atoms, which is substituted with 1or 2 substituents selected from —C(O)OH, —CH₂C(O)OH, —P(O)(Me)OH,—P(O)(OH)₂, —S(O)₂OH, —OH, and —CH₂OH.
 7. The compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein: D is K; and K is —SO₂OH, —P(O)(OH)(R^(d)),—P(O)(OH)(OR^(d)), —CH₂P(O)(OH)(OR^(d)), —C(O)NHSO₂(R^(d)), or—SO₂NHC(O)(R^(d)).
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: Dis —Z—NR⁵R⁶.
 9. The compound of claim 8, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R⁵is C₆-C₁₀ alkyl that is substituted by 5 to 9 —OH groups.
 10. Thecompound of claim 8, or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, wherein: R⁵ is C₁₋₁₀ alkyl which issubstituted by 1-6 groups selected from —N(R^(e))₃ ⁺ and K; or with 2-6groups selected from —CO₂H, —OH, and —N(R^(d))₂; and is optionallyfurther substituted by 1, 2, or 3 R^(f) groups; each R^(f) isindependently halogen, —CN, —OH, —OR¹³, —NR¹⁴R¹⁴, —C(O)OR¹⁴,—C(O)NR¹⁴R¹⁴, —NR¹⁴C(O)R¹⁴, —NR¹⁴C(O)NR¹⁴, R¹⁴, C₁-C₆ alkyl, C₃-C₆cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, isunsubstituted or substituted by 1, 2, or 3 halogen or —OH groups; and Kis —SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂, —P(O)(OH)(Me), —P(O)(OH)(H), or—P(O)(OH)(OMe).
 11. The compound of claim 8, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R⁵is [(C(R^(d))₂)_(s)—V]_(t)—R⁹; wherein each V is independently—C(R^(d))₂O—, —C(R^(d))₂NR^(d)—, —N(R^(d))—C(O)—N(R^(d))—, or—C(O)N(R^(d))—; each R^(d) is independently hydrogen or C₁₋₆ alkyl; R⁶is hydrogen or C₁₋₆ alkyl; R⁹ is hydrogen, C₁₋₈ alkyl, phenyl, ornaphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted orsubstituted by 1-6 groups selected from —OH, —CO₂H, —N(R^(e))₂,—N(R^(e))₃ ⁺, and K; and K is —SO₂OH, —P(O)(OH)₂, —CH₂P(O)(OH)₂,—P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).
 12. The compound ofclaim 8, or a pharmaceutically acceptable salt, solvate, stereoisomer,or prodrug thereof, wherein: R⁵ and R⁶ are taken together with thenitrogen to which they are attached to form a 4- to 6-memberedN-heterocycloalkyl which is substituted with 2-4 groups selected from—OH and —CH₂OH.
 13. The compound of claim 1, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:


14. A compound selected from: 1:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide;2:(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid; 3:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide;4:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol;5:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid; 6:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonicacid; 7:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)-2-(4-chlorophenyl)propane-1-sulfonicacid; 8:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid; 9:2-(N-(2-amino-2-oxoethyl)-4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonicacid; 10:5-((2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)amino)naphthalene-1-sulfonicacid; 11:4-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)benzenesulfonicacid; 12:(4′-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid; 13:(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)phosphonicacid; 14:(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)phosphonicacid; 15:3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonicacid; 16:(4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonicacid); 17:(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2,3-dihydro-1H-inden-2-yl)phosphonicacid; 18:(S)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-3-(4-(phosphonomethyl)phenyl)propanoicacid; 19:N-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(phosphonomethyl)glycine;20:3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)pentanedioicacid; 21:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-4-(hydroxy(methyl)phosphoryl)butanoicacid; 22:3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-hydroxypropanoicacid; 23:((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-L-asparticacid; 24:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)hexane-1,2,3,4,5-pentaol; 25:(2R,3R,4R,5S)-1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; 26:(4-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)butyl)phosphonicacid; 27:((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonicacid; 28:((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(phosphonomethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonicacid; 29:2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)-N,N,N-trimethylethan-1-aminium;30:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide;31:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide;32:1-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)-1,4-diazabicyclo[2.2.2]octan- 1-ium; 33:1-(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)-1,4-diazabicyclo[2.2.2]octan- 1-ium; 34:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(1,3-dihydroxypropan-2-yl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide; 35:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(2-hydroxyethyl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide;36:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol;37:4-(((4′-(6-chloro-2-((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-hydroxyethyl)butanamide;38:4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(1,3-dihydroxypropan-2-yl)butanamide; 39:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)-N,N,N-trimethylethan-1-aminium;40:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)propane-1,3-diol; 41:1-(2-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)-3-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)urea;42:(1R,2S,3R,5R)-3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol;43:(2R,3R)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)butane-1,3-diol;44:2-(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)guanidine;45:(4′-(6-chloro-2-(((3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid; 46:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide;48:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-carboxamide;49:(3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3 -ol; 50:(3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-(3-(2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;51: (3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-(4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;52:(1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol; 53:2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol;54:(1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol;55:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(4-(hydroxymethyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;56:(3R,3aR,6R,6aR)-6-(6-chloro-5-(4′-(4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;57:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;58:(3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;59:(R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidin-3-ol;60:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol;61:(3S,4R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol;62: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′4(2-(2-hydroxyethoxy)ethyl)(methyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;63: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((3-(hydroxymethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;64:(3S,4S)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol;65:(2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol;66:(1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol;67:(3R,3aR,6R,6aR)-6-((5-(4′-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;68:(4′-(6-chloro-2-(((3R,4S,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonicacid; 69: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-sulfonicacid; 70:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-sulfonamide;71:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide;72:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-sulfonamide;73:(2R,3R,4R,5S)-6-((1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)ethyl)amino)hexane-1,2,3,4,5-pentaol;74: (3R,3aR,6R,6aR)-6((6-chloro-5-(2′-hydroxy-4′4(2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol;and 75:4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide;or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.
 15. A pharmaceutical composition comprising a compound of claim1, or a pharmaceutically acceptable salt, solvate, stereoisomer, orprodrug thereof, and at least one pharmaceutically acceptable excipient.16. A method of treating an adenosine 5′-monophosphate-activated proteinkinase (AMPK) associated condition or disorder in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.
 17. The method of claim 16, wherein the condition or disorderis associated with systemic infection and inflammation from having aleaky gut barrier.
 18. The method of claim 16, wherein the condition ordisorder is metabolic syndrome, obesity, type 2 diabetes, coronaryartery disease, fatty liver, nonalcoholic steatohepatitis (NASH),cirrhosis, hepatic encephalopathy, scleroderma, inflammatory boweldisease, Crohn's disease, ulcerative colitis, checkpointinhibitor-induced colitis, psoriasis, celiac disease, necrotizingenterocolitis, gastrointestinal injury resulting from toxic insults,environmental enteric dysfunction, allergy, graft vs. host disease,irritable bowel syndrome, spontaneous bacterial peritonitis, ischemiccolitis, sclerosing cholangitis, Alzheimer's disease, Parkinson'sdisease, cancer, depression, or a combination thereof.
 19. The method ofclaim 18, wherein the allergy is food allergy, celiac sprue, orchildhood allergy, or a combination thereof.
 20. A method of treatinggastrointestinal injury resulting from toxic insult, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof.
 21. The method of claim 20,wherein the toxic insult is from radiation, chemotherapy, or acombination thereof.